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Hartmann KE, Jerome RN, Lindegren ML, et al. Primary Care Management of Abnormal Uterine Bleeding [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Mar. (Comparative Effectiveness Reviews, No. 96.)
This publication is provided for historical reference only and the information may be out of date.
Background
Condition
Abnormal uterine bleeding (AUB) is among the most common of gynecologic complaints from reproductive-age women in ambulatory care settings—of similar frequency to the number seeking care for urinary tract infections and vaginitis. In the general population, AUB is estimated to affect 11 to 13 percent of reproductive-age women. The prevalence of AUB increases with age, reaching 24 percent in women aged 36 to 40.1,2 In addition to gynecologists, all primary care practitioners including pediatricians, family physicians, advanced practice nurses, and internists, will encounter the need to evaluate, treat, or refer women with bleeding-related symptoms.3 Women generally present because the amount, timing, or other characteristics of the bleeding have changed from their individual norm.
Population norms for menstrual bleeding, as established by 5th and 95th percentiles, are:4-7
- Frequency of menses within a 24 to 38 day window
- Regularity (cycle-to-cycle variation) within 2 to 20 days
- Duration of flow from 4 to 8 days
- Volume of blood loss from 5 to 80 ml
Symptoms outside this range or different from normal for the individual can become problematic and deserve evaluation because they can warn of underlying conditions. Common problems include worry about the cause, embarrassment if the bleeding includes flooding-type bleeding with saturation of clothing, missed work and responsibilities, limitations of social activities and exercise, decreases or changes in sexual activity, and frustration with costs of sanitary protection.1,8 Collectively, the effects of troublesome bleeding reduce quality of life and drive desire for information about causes and treatment options.1,8
There is not a clear consensus on the clinical evaluation of a patient presenting with abnormal bleeding. Recommendations suggest that initial evaluation confirm the source and timing of bleeding, and exclude certain architectural etiologies, cancer, coagulation defects, and systemic disease. The 2011 International Federation of Gynecology and Obstetrics (FIGO) classification recommends a structured history followed by uterine evaluation.9 In the research setting, the alkaline hematin method is the preferred technique for direct measurement of total menstrual blood loss (MBL). The pictorial blood loss assessment chart is a semi-quantitative tool for uniform reporting of bleeding as represented by the degree of saturation of sanitary pads and tampons. Diagnostic tools and evaluation strategies are not within the scope of this review;10,11 however, the review captures the operational definitions used by researchers and addresses applicability of the findings to contemporary practice.
Terminology
Nomenclature to classify symptomatic problem bleeding has evolved steadily over the past several decades.12 Early classifications primarily used characteristics of the bleeding to group women. Terms like menorrhagia (abnormally long or heavy menses) and metrorrhagia (bleeding at irregular intervals) were often linked with timing (short or long intervals) and amount (heavy or light) to infer whether or not regular and predictable ovulation was occurring and further assign likely ovulatory or anovulatory status. These terms are generally applied without formal documentation of ovulatory status. Furthermore, previously applied terms like “dysfunctional uterine bleeding” also carried a variable element of recognition that the label was a diagnosis of exclusion.12 The resulting challenge was that practitioners and researchers applied different exclusions before selecting interventions or enrolling patients. Over time, differences in terminology choice and in operational definitions have resulted in wide inconsistencies in application of diagnostic terms.4,12-14
Recent international consensus recommendations, formally adopted by FIGO in 2010 and published in 2011, more consistently align terminology by creating two major groupings (i.e., discrete structural vs. nonstructural) for causes of bleeding.9,15,16 The FIGO classification includes nine categories of abnormal bleeding arranged according to the acronym PALM-COEIN:9,16 four have objective visual criteria detected by imaging, biopsy, or pathology (i.e., PALM: polyps; adenomyosis; leiomyomata; and malignancy and hyperplasia) while another five are not directly related to structural abnormalities (i.e., COEIN: coagulopathy; ovulatory dysfunction; endometrial; iatrogenic; and not yet classified).
If we map the intended focus of this comparative effectiveness review (CER) to the FIGO classification, we are addressing the COEIN groups that are characterized as “ovulatory dysfunction” (AUB-O), “endometrial hemostatic dysfunction” (AUB-E), and “not yet classified” (AUB-N) abnormal bleeding. However it is crucial to note that direct measures of ovulation are not employed in most available literature and endometrial samples for classification are even more rare, except when used to rule out malignancy. Indeed much remains to be explained about the pathophysiology of the very common and problematic complaint of unpredictable and/or heavy bleeding. In summary, the relevant population for this review includes nonpregnant women from menarche to menopause who have had abnormal bleeding (scant or heavy) for 3 months or longer that is not attributed to structural abnormalities, coagulation defects, systemic illnesses, or medications.
While some reviews further subdivide women experiencing AUB into age groups,17 such as those near menarche and in the perimenopausal timeframe, we plan to retain an emphasis on categorization. Women across the reproductive lifespan can have abnormal bleeding that arises from ovulatory dysfunction or endometrial processes.18 While the underlying causes may vary, for instance from lack of consistent regulation of the hypothalamic-pituitary-ovarian axis in teens near the onset of menses, and from lack of ovarian reserve in perimenopausal women, the treatment options overlap.3 We will report when research was done with an age-restricted population but will otherwise cover all the relevant literature regardless of reproductive age or reproductive history of participants.
Therapies
Current guidelines from professional societies including the American Congress of Obstetricians and Gynecologists,19-22 the American Academy of Family Physicians,23 and the National Institute for Clinical Excellence24 recommend medical therapy, including the levonorgestrel-releasing intrauterine system (LNG-IUS), nonsteroidal anti-inflammatory drugs (NSAIDs), antifibrinolytics, combined oral contraceptives (COCs), and progestogens, as the first-line treatment for irregular uterine bleeding and abnormal cyclic bleeding.
In a recently published research article,25 Matteson and colleagues examined the practice patterns and attitudes from a U.S. sample of obstetricians and gynecologists regarding the medical treatment of women with AUB. The authors reported that practicing obstetrician-gynecologists most frequently selected COCs for the treatment of both irregular and abnormal cyclic menstrual bleeding and that participants lacked an overall awareness of current evidence on effectiveness of common treatment options for AUB.25 However, another recent publication26 reported that, that in conflict with recommendations, uterine-preserving surgical procedures were the most common first-line treatment for women with heavy menstrual bleeding within a large cohort from a national claims database of large employers.
Primary Care Treatment Options
Pharmacologic therapies to treat AUB in the ambulatory setting include estrogens, progestogens, combination (estrogen and progestogen) hormonal formulations, NSAIDs, antifibrinolytics, and progesterone-releasing intrauterine devices (IUDs). Medical interventions are generally considered first-line treatment.27,28 Surgical intervention is usually reserved for women with persistent bleeding that does not respond to medical therapy or for women who have finished childbearing and do not wish to continue medical therapy indefinitely.2,23
LNG-IUS
A pooled analysis of data from five randomized controlled trials (RCTs) reported that the LNG-IUS provided clinically and statistically significant sustained reductions in MBL.29 Locally released progesterone from the IUD reduces growth of the uterine lining, minimizing the tissue available to be shed during menstruation. IUDs are used as contraception by approximately 5 percent of women in the United States.30 Based on large-scale claims data, use of the LNG-IUS increased 19-fold between 2002 and 2008 to 7.7 per 1000 women, becoming the most commonly used IUD in the United States.31
NSAIDs
NSAIDs are commonly used to treat AUB (more recently termed AUB-E) because of the role of prostaglandins in the pathogenesis of heavy menstrual bleeding. Higher levels of prostaglandin E2 have been observed in the endometria of women with heavy menstrual bleeding.32 Additional evidence points to an abnormal ratio of specific prostaglandins as a contributing factor to problems with hemostasis.32 NSAIDs act to reduce prostaglandin synthesis by inhibiting the enzyme cyclo-oxygenase and therefore reducing endometrial prostaglandin levels leading to decreased potential for vasodilation and angiogenesis.33 Based on a limited number of small studies, a 2007 Cochrane Review34 found that NSAIDs were superior to placebo but less effective than tranexamic acid and LNG-IUS at reducing MBL.
TXA
TXA is an antifibrinolytic that slows the breakdown of fibrin in blood clots. By decreasing the degradation of physiologic blood clots, blood flow from uterine vessels sealed by the clot is decreased. Since it is not a hormonal agent and does not have contraceptive effects it may be useful for women who desire a pregnancy or for whom hormonal treatment is contraindicated. TXA appears to be well-tolerated and cost-effective, reducing blood loss considerably and improving health related quality of life for women with menorrhagia.35
COCs
COCs are commonly used to manage abnormal bleeding associated with ovulation since they work in part by superimposing an organized cycle and discourage thick growth of the uterine lining. The American Congress of Obstetrics and Gynecologists 2010 Practice Bulletin for noncontraceptive uses of hormonal contraceptives recommends COCs as a reasonable choice to regulate and reduce menstrual bleeding, based on good and consistent scientific evidence.21 However, according to a 2009 Cochrane systematic review,36 there is insufficient evidence to establish the effectiveness of the oral contraceptive pill compared with other medical therapies, placebo, or no therapy for the treatment of heavy menstrual bleeding.36 In a clinical review for diagnosis and management of AUB,37 authors assert that COCs are likely beneficial for treatment of anovulatory (i.e., acyclic) AUB but there is lack of good quality data to support their use in abnormal cyclic bleeding.37 The COC is also known to cause abnormal bleeding patterns, with breakthrough bleeding reported as one of the most common reasons for discontinuation of COC use.38 Additional data are needed on the number needed to treat and the number needed to harm for adverse effects.
Progestogens
During a normal cycle, the natural rise and fall of progesterone, which is produced by the ovary after ovulation, has multiple biological effects on the endometrium. These include “organization” that results in the coordinated withdrawal bleeding observed as the menses after progesterone levels fall. Cyclic administration of progestogens in women with AUB is intended to mimic natural production of progesterone in the luteal phase and then withdrawal, by providing the agent for a number of days, typically 10 to 14, after which bleeding occurs. Other methods of administration of progestogen, such as by long acting injection or oral contraceptive pills that contain only a progestogen, exploit a different biologic property of progestogens. When continuously administered, progestogens encourage endometrial quiescence and reduce growth of the endometrium. In women with AUB, these effects can modulate problematic symptoms by fostering endometrial stability and a relatively thin endometrium resulting in less bleeding. The American Congress of Obstetrics and Gynecologists practice bulletins on management of anovulatory bleeding and noncontraceptive uses of hormonal contraceptives note that progestogens are an appropriate first-line choice for medical management of irregular bleeding that results from lack of regular, predictable ovulation.19,21
Behavioral and Lifestyle Interventions
Diet and physical activity interventions have been proposed for irregular menstrual bleeding because irregular menses often indicate irregular or absent ovulation. Obesity and metabolic syndrome, including polycystic ovarian syndrome (PCOS), are associated with increased risk of anovulatory cycles. Trials that have achieved modest weight loss in infertile patients have restored regular ovulatory function in a majority of women with obesity-related subfertility.39 Both aerobic and strength training as well as weight loss may improve blood sugar profiles and reduce relative or frank insulin resistance, which are intermediates to restoring regular menses in some women.
Complementary and Alternative Medicine
Initial literature scans suggested that there is an extremely limited body of literature on trials of complementary and alternative medicine for AUB. Complementary and alternative medicine based therapies are included as interventions of interest due to their increasing popularity among patients and growing interest to clinicians.40
Scope and Key Questions
Scope of the Review
The relevant population for this review includes nonpregnant women from menarche to menopause who have had AUB for 3 months or longer, that is not attributed to structural abnormalities, coagulation defects, systemic illnesses, or medications.
The literature reflects various management options for women with AUB with conflicting recommendations/summaries. Interventions of interest for this review include medical, complementary and alternative medicine, and behavioral/lifestyle interventions. This review does not consider surgical interventions for AUB, as surgical management is adequately covered by other groups conducting systematic reviews.
This review is focused on the evidence available to inform selection of nonsurgical options to treat AUB with an emphasis on interventions that are accessible to and within the scope of usual practice for primary care practitioners in a clinical care setting. This means that while we did not restrict literature review to studies conducted only in primary care settings, we did restrict the review to include only those interventions that could be deployed in primary care. We address abnormal bleeding that is chronic in nature, meaning the symptom has persisted for the majority of the prior 3 months, and is of two primary and common types: (1) irregular in timing (i.e., acyclic); and (2) abnormal though cyclic. We explicitly defined eligibility criteria using a PICOTS (population, intervention, comparator(s), outcome, timing, and setting) structure (Table 1).
Table 1
PICOTS.
Key Questions
Key Question 1A (KQ1A)
What is the evidence for the effectiveness of medical, behavioral, and complementary and alternative medicine interventions (e.g., hormonal treatment, weight loss, or acupuncture) for improving short and long-term outcomes in women with irregular uterine bleeding?
Key Question 1B (KQ1B)
What is the evidence for the effectiveness of medical, behavioral, and complementary and alternative medicine interventions (e.g., hormonal treatment, weight loss, or acupuncture) for improving short and long-term outcomes in women with abnormal cyclic uterine bleeding?
Key Question 2 (KQ2)
What are the harms, including adverse events, associated with medical, behavioral, and complementary and alternative medicine interventions (e.g., hormonal treatment, weight loss, or acupuncture) in women with irregular uterine bleeding or abnormal cyclic uterine bleeding?
Analytic Framework
We developed the analytic framework (Figure 1) drawn from clinical expertise of Key Informants and refined it with input from a Technical Expert Panel (TEP). The analytic framework illustrates the population, interventions, outcomes, and adverse effects that guided the literature search, study eligibility, screening, and synthesis.
Figure 1
Analytic framework. CAM = complementary and alternative medicine Note: Numbers in circles represent Key Questions.
Organization of This Report
The Methods chapter describes our processes including our search strategies, inclusion and exclusion criteria, approach to review of abstract and full publications, methods for extraction of data into evidence tables, and compiling evidence. We also describe our approach to grading the quality of the literature and assessing the strength of the evidence.
The Results Chapter presents the findings of the literature search and review of the evidence by Key Question (KQ). When there are distinct populations in which the interventions have been studied such as enrollment based on differing criteria, we discuss related data together. Within KQs we present summary information in the order: devices, medications, lifestyle and behavior interventions, and complementary and alternative medicine. Within a category such as medication, we organize the results from greater number of studies to fewer, and presented the results of placebo controlled trials before direct comparisons.
The final section discusses the results and enlarges on the methodologic considerations relevant to each KQ. We also outline the current state of the literature and needs for future research on management of AUB. We include a list of abbreviations and acronyms at the end of the report followed by appendixes to provide further detail on our methods and the studies assessed. The appendices are as follows:
- Appendix A Literature Search Strategies
- Appendix B Abstract Review Form (KQ1)
- Appendix C Abstract Review Form (KQ2)
- Appendix D Full-Text Review Form (KQ1)
- Appendix E Full-Text Review Form (KQ2)
- Appendix F Cochrane Risk of Bias Tool
- Appendix G Cochrane Risk of Bias Criteria
- Appendix H Thresholds for Quality Assessment
- Appendix I Risk of Bias and Quality Score for Individual Studies
- Appendix J Evidence Table
- Appendix K Reasons for Exclusion (KQ1)
- Appendix L Reasons for Exclusion (KQ2)
- Appendix M Labeled Indications for Drugs Included in Review
- Appendix N Harms from Package Inserts for Drugs Included in Review
- Appendix O Systematic Reviews
- Appendix P Ongoing Studies
- Introduction - Primary Care Management of Abnormal Uterine BleedingIntroduction - Primary Care Management of Abnormal Uterine Bleeding
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