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GUIDELINES
ABNORMAL UTERINE BLEEDING Second Edition, November 2009 ! ! !
November 2009 ! !
Technical Working Group for the Clinical Practice Guidelines On Abnormal Uterine Bleeding
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Philippine Obstetrical and Gynecological Society (Foundation), Inc (POGS)
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CLINICAL PRACTICE GUIDELINES on ABNORMAL UTERINE BLEEDING
November 2009!
Technical Working Group for the Clinical Practice Guidelines On Abnormal Uterine Bleeding
FOREWORD" !
LOURDES B. CAPITO, MD President Philippine Obstetrical and Gynecological Society (Foundation), Inc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INTRODUCTION"
" EFREN J. DOMINGO, MD, PhD Chair, AdHoc Committee on the Clinical Practice Guidelines, 2009
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I. DEFINITION OF TERMS Statement 1 Abnormal uterine bleeding (AUB) encompasses any significant deviation from normal frequency, regularity, heaviness (volume or amount) and duration of menstrual bleeding. It is used to describe all abnormal menstrual signs and symptoms arising from the uterine corpus. (III, C) Reference: 1. Fraser IS (2007) What do we mean by abnormal uterine bleeding and dysfunctional uterine bleeding? Gynecol Forum 12:2, 3-5.
Statement 2 The normal limits for the four main clinical dimensions of menstruation and the menstrual cycle (regularity, frequency, duration and volume or amount) are outlined below. Based on these limits, AUB may include short or long (but regular) menstrual cycles, irregular menstrual cycles, heavy or light menstrual periods, intermenstrual bleeding, premenarcheal or postmenopausal bleeding, with or without any recognizable pathology. Normal limits for menstrual parameters in the mid-reproductive years (III, C) (Modified from the Consensus Meeting of Clinicians and Scientists (2007) by Frasier IS, Critchley HOD, Munro MG, Broder M. Hum Reprod, 1-9.)
Clinical Dimensions of Menstruation Descriptive and Menstrual Cycle Terms Frequency of menses (days) Frequent Normal Infrequent Regularity of menses (cycle to cycle Absent variation over 12 months; in days) Regular Irregular Duration of flow (days) Prolonged Normal Shortened Volume of monthly blood loss (ml) Heavy Normal Light
Normal Limits (5th-95th percentiles) < 24 24-38 > 38 Variation of 2 to 20 days Variation > 20 days > 8.0 4.5-8.0 < 4.5 > 80 5-80 <5
Supporting Statements: Suggested normal limits for the four main clinical dimensions of menstruation and the menstrual cycle (regularity, frequency, duration and flow) are set on the basis of medians and 95% confidence intervals. These have been developed following the consensus meeting of clinicians and scientists in Washington1, based primarily on the independent WHO analysis2, and also on other published population data3-6.
References:
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1. Frasier IS, Critchley HOD, Munro MG, Broder M (2007) Can we achieve international agreement on terminologies and definitions used to describe abnormalities of menstrual bleeding? Hum Reprod, 1-9. 2. Belsey EM and Pinol AP, World Health Organization Task Force on Long-Acting Systemic Agents for Fertility Regulation (1997) Menstrual bleeding patterns in untreated women. Contraception 55, 57-65. 3. Hallberg L, Hogdahl AM, Nilsson L and Rybo G (1966) Menstrual blood loss: a population study. Acta Obstet Gynecol Scand 45, 320-351. 4. Treloar AE, Boynton RE, Behn BG and Brown BW (1967) Variation of the human menstrual cycle through reproductive life. Int J Fertil 12, 77-126. 5. Snowden R and Christian B (eds) (1983) Patterns and Perceptions of Menstruation (A World Health Organization international study). Croom Helm, London, p.339. 6. Fraser IS and Inceboz US (2000) Defining disturbances of the menstrual cycle. In: O’Brien PMS, Cameron IT and Maclean AB (eds). Disorders of the menstrual cycle. London: RCOG Press, 141-52.
Statement 3 It is recommended that the term menorrhagia be discarded and replaced by the term “heavy menstrual bleeding”. (III, C) Supporting Statements: The most common clinically significant disturbance in uterine bleeding is abnormally heavy bleeding. The term menorrhagia is used to describe such heavy bleeding, but its exact use is variable. It is usually used to describe a symptom, but some clinicians use it as a diagnosis. Thus, it is recommended that this term, along with other terms such as hypermenorrhea, metrorrhagia and menometrorrhagia, be abandoned1-2. The current popular term for heavy menstruation is heavy menstrual bleeding3. References: 1. Fraser IS and Inceboz US (2000) Defining disturbances of the menstrual cycle. In: O’Brien PMS, Cameron IT and Maclean AB (eds). Disorders of the menstrual cycle. London: RCOG Press, 141-52. 2. Frasier IS, Critchley HOD, Munro MG, Broder M (2007) Can we achieve international agreement on terminologies and definitions used to describe abnormalities of menstrual bleeding? Hum Reprod, 1-9. 3. National Institute for Health and Clinical Excellence (NICE). Heavy menstrual bleeding (2007).
Statement 4 Dysfunctional uterine bleeding (DUB) is defined as excessive bleeding of uterine origin that is not due to complications of pregnancy or to any systemic or local pelvic pathology. It has been used as a diagnosis of exclusion. Ovulatory DUB is described as having regular cycles with heavy bleeding. On the other hand, anovulatory DUB is characterized by irregular, prolonged and/or heavy bleeding. (GPP) Supporting Statements: DUB is commonly used to describe abnormally heavy or irregular bleeding without recognizable organic pathology1-2. In Europe, DUB is further differentiated into ovulatory and anovulatory DUB; while in USA, DUB usually connotes anovulatory cycles. It is a term used when the disorder involves primarily the endometrial molecular mechanisms (ovulatory DUB) or the hypothalamic-pituitary-ovarian axis (anovulatory DUB).3 e"
The recent FIGO 2009 Congress recommended that the term DUB should be discarded. The justifications for abolishing the term ‘DUB’ are as follows4: • A diagnosis of exclusion and admission of our ignorance about local mechanisms • Terminology used very differently in different countries (symptoms, signs, diagnoses) • “old DUB” includes the following – coagulopathies (congenital and acquired), ovulatory disorders and endometrial dysfunction (infection, disturbances of local hemostasis, inflammation, vasoactive regulators) The Technical Working Group for the POGS 2009 Clinical Practice Guidelines on Abnormal Uterine Bleeding concurs with the FIGO recommendation. References: 1. Fraser IS (1985) The dysfunctional uterus- dysmenorrhea and dysfunctional uterine bleeding. In: Shearman RP, ed. Textbook of clinical reproductive endocrinology. Edinburgh: Churchill Livingstone, 578-98. 2. Crosignani PG and Rubin B (1990) Dysfunctional uterine bleeding. Hum Reprod 5: 637-8. 3. Fraser IS (2007) What do we mean by abnormal uterine bleeding and dysfunctional uterine bleeding? Gynecol Forum 12:2, 3-5. 4. Fraser IS et al. FIGO 2009 Congress Interactive Session on AUB, Cape Town International Convention Center, South Africa. 6 October 2009.
Statement 5 AUB includes both DUB and bleeding from organic causes. (III, C) Supporting Statements: When AUB is due to systemic causes or disorders of the reproductive tract, the etiology is described as organic. The absence of organic pathology makes the cause of bleeding as dysfunctional1-2. References: 1. Lindeque BG (2007) Clinical approach to a patient with abnormal uterine bleeding. SA Fam Pract 49(8): 32-33. 2. Ely JW, Kennedy CM, Clark EC and Bowdler NC (2006) Abnormal uterine bleeding: a management algorithm. J Am Board Fam Med; 19: 590-602.
Statement 6 Acute AUB is characterized by significant blood loss that results in hypovolemia (hypotension or tachycardia) or shock. (GPP) Supporting Statements: Acute uterine bleeding ranges from modestly heavy menstrual bleeding to excessively heavy bleeding associated with hypovolemic shock.1,2,5 It occurs more frequently in anovulatory women.3,4 Acute uterine bleeding requires urgent or emergent medical intervention that more often leads to frequent use of urgent care, emergency and operating room resources. References: 1. Munro MG. Acute uterine bleeding unrelated to pregnancy. Gynaecol Forum 2007; 12(2): 1114.
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2. 3. 4. 5.
Speroff L, Glass RH, Kase NG. Clinical gynecologic endocrinology and infertility. 6th ed. Baltimore: Lippincott Williams & Wilkins 1999; 21-38,499,575-9. Word RA, Kamm KE, Casey ML. Contractile effects of prostaglandins, oxytocin, and endothelin-1 in human myometrium in vitro: refractoriness of myometrial tissue of pregnant women to prostaglandins E2 and F2 alpha. J Clin Endocrinol Metab 1992; 75: 127-32. Livingston M, Fraser IS. Mechanisms of abnormal uterine bleeding. Hum Reprod Update 2002; 8: 60-7. Fraser IS et al. FIGO 2009 Congress Interactive Session on AUB, Cape Town International Convention Center, South Africa. 6 October 2009.
Statement 7 Chronic AUB is bleeding from the uterine corpus, that is abnormal in duration, volume, regularity, and/or frequency and has been present for the majority of the last six (6) months. (GPP) References: 1. Fraser IS et al. FIGO 2009 Congress Interactive Session on AUB, Cape Town International Convention Center, South Africa. 6 October 2009.
II. PATHOPHYSIOLOGY A. Normal Menstruation: •
Factors that come into play for hemostasis: 1) a higher thromboxane level (PGF2) in relation to prostacyclin (PGE2 ) 2) fibrin clot formation, and 3) stabilization of the hemostatic platelet plug. The absence of any, or all of these factors may result in heavier menstruation.
B. Abnormal Uterine Bleeding (AUB) Etiology of Abnormal Uterine Bleeding 1. Organic Causes a. Reproductive Tract Disease i. Pregnancy related complication •
Pregnancy is the first consideration in women of reproductive age who present with AUB. Potential causes of pregnancy-related bleeding include: o spontaneous pregnancy loss o ectopic pregnancy o placenta previa o abruptio placentae o hydatidiform mole o choriocarcinoma
ii. Non-pregnancy related genital lesions (benign or malignant pelvic lesions) M"
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Non-pregnancy related genital causes include: o Myomas o Endometrial carcinoma, polyps or hyperplasia o Chronic cervicitis o Cervical polyps & carcinomas o Vaginal carcinoma o Functional ovarian cysts or neoplasms
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Bleeding from a secretory endometrium, which indicates ovulation, usually implies an anatomic lesion rather than an endocrine disorder, although ovulatory bleeding may occasionally produce minimal midcyclic bleeding in the absence of an organic lesion.
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Myomas and polyps are widely recognized structural abnormalities causing abnormal uterine bleeding, but the precise mechanisms by which they increase bleeding are poorly understood.
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The abnormal bleeding associated with submucous myomas typically begins as prolonged menses, which may be sufficiently severe to cause anemia. It has been suggested that myoma-related AUB may result from: o an increased surface area of the endometrium due to mechanical distortion o ulceration and hemorrhage of endometrium overlying the submucous fibroids o interference by the myomas with normal uterine hemostasis o mechanical compression of the venous drainage by the myomas at any site, and o dilatation of the venous plexuses draining the endometrium
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Submucous myomas are highly vascularized, with large, fragile vessels on their surfaces. Bleeding from these large-caliber vessels during menstruation cannot be stopped promptly by myometrial contractions because of their intracavitary position.
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The association of adenomyosis with AUB is controversial and remains unclear. However, several hypotheses have been introduced and these include: o an increased endometrial surface o altered PGE/PGF ! balance o hampered myometrial contractility o abnormal myometrial angionesis associated with fragile blood vessels.
•
Endometrial polyps are found in all age groups, but mostly in older women, and may also present as heavy menstrual, intermenstrual, or postmenopausal bleeding and may be associated with dysmenorrhea.
•
Arteriovenous malformations, despite their rare occurrence, contribute to the problem of AUB and should therefore be included in the differential diagnosis of women with acute, heavy menstrual bleeding.
•
Genital tract infections, particularly Chlamydia trachomatis infection should likewise be considered among women who presents with irregular bleeding and post-coital spotting.
b. Systemic Disease •
Non-pregnancy-related systemic disorders (i.e. neoplasms, metabolic, organic, and other anatomic causes must be ruled out): o Blood dyscrasias o Thrombocytopenia o Deficient clotting factors o Thyroid dysfunction o Hepatic dysfunction o Renal dysfunction
•
AUB, particularly in premenarcheal girls, may be suggestive of an inherited systemic disorder of hemostasis. A meta-analysis of high-quality epidemiological prevalence studies indicated a 13% prevalence rate of the biochemical markers of von Willebrand disease among women with heavy menstruation.
•
AUB is likewise associated with hypothyroidism. Hyperthyroidism, hypothalamic dysfunction, hyperprolactinemia, premature ovarian failure, and primary pituitary disease are, most often than not, associated with amenorrhea and rarely result in heavy bleeding.
•
Diabetes mellitus can be associated with anovulation, obesity, insulin resistance, and androgen excess, and increases the likelihood of abnormal uterine bleeding.
•
Renal or liver diseases may also result in abnormal uterine bleeding. Women with liver disease may have higher circulating levels of estrogen due to hepatic dysfunction and an inability to metabolize estrogen. Coagulopathies also may occur with liver disease, while renal failure is associated with irregularities of the HPO axis due to gonadal resistance to hormones, platelet dysfunction, and abnormal factor VIII activity.
c. Iatrogenic •
AUB among women on contraceptive hormones are usually manifested as irregular bleeding, and may result from an inconsistent use, or, more commonly, as a “breakthrough” bleeding especially during the first few months of hormonal contraceptive use. However, not all bleeding that occurs in this group of women can be attributed to hormonal contraceptive use.
•
Women on chronic use of steroids, anticoagulants, tranquilizers, digitalis, dilantin and/or IUD may manifest with AUB.
2. Dysfunctional (or Endocrinologic) Causes (anovulatory or ovulatory dysfunctional uterine bleeding) WW"
•
Dysfunctional uterine bleeding (DUB) is usually anovulatory and is associated with a non-secretory endometrium. It is most common after the menarche or just before the menopause, but it may occur at other times as well.
•
In puberty, the HPO axis has not yet developed the necessary hormonal feedback to sustain the endometrium.
•
In perimenopause, the decline of inhibin and rise in follicle-stimulating hormone (FSH) levels reflect the loss of follicular activity and competence.
•
Prolonged DUB may result from a persistent graafian follicle. In such cases, withdrawal of estrogen leads to a delayed endometrial shedding and irregular bleeding. The bleeding is caused by estrogenic overstimulation followed by withdrawal or diminution of estrogen, unopposed by progesterone.
•
High sustained levels of estrogen result in episodes of amenorrhea followed by acute heavy bleeding. Healing within the endometrium is irregular and dyssynchronous.
•
Abnormal uterine bleeding may reflect a disordered regulation of endometrial gene expression.
•
Despite a wealth of studies on this very common clinical entity, explanations on many of the cellular and molecular alterations in endometrial pathologies remain to be elusive and have yet to be fully elucidated.
References: 1. 2. 3. 4. 5. 6.
Albers JR, Huli SK, Wesley MA. Abnormal Uterine Bleeding. Am Fam Physician 2004; 69:1915-26; 1931-2. Berek JS. Berek & Novak’s Gynecology. 14th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2007. Garefalakis M, Hickey M. Present understanding of abnormal uterine bleeding mechanisms. Gynaecology Forum 2007 Vol. 12, No. 2: 6-8. Lukes AS. The role of disorders of hemostasis and abnormal uterine bleeding. Gynaecology Forum 2007 Vol. 12, No. 2: 14-19. Munro MG. Acute uterine bleeding unrelated to pregnancy. Gynaecology Forum 2007 Vol. 12, No. 2: 11-14. Wynn RM. Obstetrics and Gynecology the clinical core. 5th ed. Philadelphia, PA: Lea & Febiger, 1992.
III. EPIDEMIOLOGY •
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Abnormalities in menstruation are a common cause of general practice consultations with considerable health-service resources devoted to their management.1
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•
Women who report one or more menstrual symptoms have significantly lower health status and quality of life compared with women reporting no menstrual symptoms.3
•
Women with heavier periods are 72% as likely to be working as women who have normal flow. Menstrual abnormalities, especially heavy periods, have significant economic implications, and work loss secondary to heavy periods has been estimated to cost $1692 per woman annually.4
•
The 12-month cumulative incidence of AUB are as follows5: o Menorrhagia 25% (95% CI 22–29%) o Metrorrhagia 29% (95% CI 26–32%) o Oligomenorrhea 15% (95% CI 13–18%) o Intermenstrual bleeding 17% (95% CI 14–19%) o Postcoital bleeding 6% (95% CI 5–8%)
•
The modern-day definition of menorrhagia is a blood loss of > 80 ml but it is of limited clinical usefulness since the diagnosis and treatment of patients appears to be unrelated to the volume of blood loss. Subjective judgment of the volume lost in combination with clinical features can predict a loss of > 80 ml.6,7
•
Menstrual problems are common during adolescence due to a relatively immature hypothalamo-pituitary-ovarian (HPO) axis leading to anovulation.8
•
Anovulation (46%) was the predominant cause of admission for adolescent menorrhagia, followed by hematological disease (33%) and unfortunately, nearly 63% of adolescents required blood transfusion in view of severe anemia.9
•
A Nepal survey of 96 school girls with an age range of 11–17 years, menorrhagia was identified in 6.2% of girls. Nearly 10% of girls gave a history of hypomenorrhea and 6.9% had oligomenorrhiec cycles.10
•
A population-based survey of 1019 Swedish girls with a mean age of 16.7 years found that nearly 37% of girls experienced menorrhagia and onefifth of them were being treated with drugs for this condition. A family history of menorrhagia was documented in 38% of girls and more than 50% of them suffered from heavy periods themselves.11
•
A postal survey of 4610 women (aged 25–44 years) in Scotland found that 30–35% of women reported menorrhagia.12
•
In a cross-sectional survey of 2262 women of reproductive age (18–45 years), moderate-to-severe dysmenorrhea was reported in 33.4% of participants (95% CI 31.4–35.4%) with the incidence of dysmenorrhea being 1.92 times higher in women with menorrhagia (95% CI 1.4–2.6).13
•
Menstrual irregularities are more common in female athletes and in those who begin training prior to menarche (43%). AUB in athletes has
significant associations with low body fat and weight and the stress of sports activity. Ball-game players (35%) and distance runners (51%) most commonly experience oligomenorrhea or amenorrhea, whereas swimmers (37%) and sprinters (41%) experience dysmenorrhea and menorrhagia.14 References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Coulter A, McPherson K & Vessey M. Do British women undergo too many or too few hysterectomies? Soc Sci Med 1988; 27: 987–994. Barnard K, Frayne SM, Skinner KM et al. Health status among women with menstrual symptoms. J Womens Health (Larchmt) 2003; 12: 911–919. Cote I, Jacobs P & Cumming D. Work loss associated with increased menstrual loss in the United States. Obstet Gynecol 2002; 100: 683–687. Shapley M, Jordan K & Croft PR. An epidemiological survey of symptoms of menstrual loss in the community. Br J Gen Pract 2004; 54: 359–363. Warner PE, Critchley HO, Lumsden MA et al. Menorrhagia I: measured blood loss, clinical features, and outcome in women with heavy periods: a survey with follow-up data. Am J Obstet Gynecol 2004; 190: 1216–1223. Warner PE, Critchley HO, Lumsden MA et al. Menorrhagia II: is the 80-mL blood loss criterion useful in management of complaint of menorrhagia? Am J Obstet Gynecol 2004; 190: 1224–1229. Quint EH & Smith YR. Abnormal uterine bleeding in adolescents. J Midwifery Womens Health 2003; 48:186–191. Smith YR, Quint EH & Hertzberg RB. Menorrhagia in adolescents requiring hospitalization. J Pediatr Adolesc Gynecol 1998; 11: 13–15. Sharma M & Gupta S. Menstrual pattern and abnormalities in the high school girls of Dharan: a cross sectional study in two boarding schools. Nepal Med Coll J 2003; 5: 34–36. Friberg B, Orno AK, Lindgren A et al. Bleeding disorders among young women: a population-based prevalence study. Acta Obstet Gynecol Scand 2006; 85: 200–206. Santer M, Warner P & Wyke S. A Scottish postal survey suggested that the prevailing clinical preoccupation with heavy periods does not reflect the epidemiology of reported symptoms and problems. J Clin Epidemiol 2005; 58: 1206–1210. Patel V, Tanksale V, Sahasrabhojanee M et al. The burden and determinants of dysmenorrhoea: a population-based survey of 2262 women in Goa, India. Br J Obstet Gynaecol 2006; 113: 453–463. Toriola AL & Mathur DN. Menstrual dysfunction in Nigerian athletes. Br J Obstet Gynaecol 1986; 93: 979–985.
IV. DIAGNOSIS Diagnosis of Heavy Menstrual Bleeding 1. History 2. Physical Examination 3. Blood Tests 4. Imaging Procedures Statement 1 Wa"
A detailed history should be obtained, which should include inquiry into the character and nature of bleeding, related symptoms that may implicate a structural or histologic abnormality, family history, contraceptive history, as well as presence of co-morbid factors. (III, C) Supporting Statements: The clinical history should focus on the probable causes of abnormal menstrual bleeding by determining the interval, amount, frequency, and duration of bleeding. Pregnancy must always be excluded. Symptoms such as intermenstrual or postcoital bleeding, pelvic pain and/or pressure symptoms, suggest structural or histologic abnormality.1 Risk factors for endometrial carcinoma should be sought. Family history should investigate risks for cancer, coagulopathies, and other medical conditions that can cause abnormal uterine bleeding.2 References 1. Penny GC. The investigation of menorrhagia. In: Disorders of the Menstrual Cycle. London: RCOG press, 2000. Chapter 16. 2. Higham JM, Page LM, Mohan S. How do we assess abnormal uterine bleeding? Gynaecology Forum 2007; 12(2): 8-10.
Statement 2 Physical examination should be performed to identify any structural pathology or systemic disease as the etiology for abnormal uterine bleeding. (III, C) Supporting Statements: General survey should include assessment for anemia, thyroid disease and coagulopathies. Abdominal palpation may detect an enlarged uterus.1 Pelvic examination to inspect the vulva, vagina and cervix is essential to exclude any gross pathology. Bimanual examination will allow assessment of the uterine size, pelvic tenderness and adnexal masses. References 1. National Collaborating Centre for Women’s and Children’s Health; National Institute for Health and Clinical Excellence. Heavy menstrual bleeding. Clinical guideline. 24 January 2007. London: RCOG Press, 2007.
Statement 3 A complete blood count should be obtained from all women with abnormal uterine bleeding. (III, C) Supporting Statements: A full blood count should be obtained to identify women with anemia. Five epidemiological studies showed that anemia is an associated problem for women with HMB.1-5 These studies show that MBL and iron-deficiency anemia are linked, with iron deficiency becoming a clinical problem at a menstrual blood loss of 60–80 ml. Iron supplements should be prescribed as needed.6 Serum ferritin level may be useful if there is any doubt on iron deficiency,7 but should not be part of routine investigation.8 References
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1. 2. 3. 4. 5. 6. 7. 8.
Looker AC, Dallman PR, Carroll MD, et al. Prevalence of iron deficiency in the United States. JAMA: the journal of the American Medical Association 1997;277(12):973–6. Hallberg L, Hogdahl AM, Nilsson L, et al. Menstrual blood loss--a population study. Variation at different ages and attempts to define normality. Acta Obstetricia et Gynecologica Scandinavica 1966;45(3):320–51. Andrade AT, Souza JP, Shaw ST Jr, et al. Menstrual blood loss and body iron stores in Brazilian women. Contraception 1991; 43(3):241–9. Janssen CA, Scholten PC, Heintz AP. Reconsidering menorrhagia in gynecological practice. Is a 30-year-old definition still valid? European Journal of Obstetrics, Gynecology, and Reproductive Biology 1998;78(1):69–72. Gao J, Zeng S, Sun BL, et al. Menstrual blood loss and hematologic indices in healthy Chinese women. Journal of Reproductive Medicine 1987;32(11):822–6. Royal College of Obstetricians and Gynaecologists. The Management of Menorrhagia in Secondary Care. National Evidence Based Clinical Guideline No 5. London: RCOG, 1999. Fraser IS. Menorrhagia – a pragmatic approach to the understanding of causes and the need for investigations. Br J Obstet Gynaecol 1994; 101(supplement 11): 3–7. National Collaborating Centre for Women’s and Children’s Health; National Institute for Health and Clinical Excellence. Heavy menstrual bleeding. Clinical guideline. 24 January 2007. London: RCOG Press, 2007.
Statement 4 Coagulation tests may be considered only in women with HMB at an early age (since menarche), and have personal or family history suggestive of a coagulopathy. (III, C) Supporting Statements: Universal screening for coagulation disorders in women with HMB is not costeffective. A review of 11 studies (988 women) on the prevalence of Von Willebrand disease in women with HMB showed that the prevalence in individual studies ranged from 5% to 24%, with an overall prevalence rate of 13% (95% CI 11.0-15.6).1 A personal and family history of bleeding symptoms is a valid reason for investigation. Any one of the following aspects in the history taking should prompt the clinician to work-up the woman for a coagulation disorder: HMB since menarche, postpartum hemorrhage, surgery-related bleeding, and/or bleeding associated with dental work.2 References 1. Shankar M, Lee CA, Sabin CA, et al. Von Willebrand disease in women with menorrhagia: a systematic review. Br J Obstet Gynaecol 2004; 111: 734-40. 2. Kouides PA, Conard J, Peyvandi F, et al. Hemostasis and menstruation: appropriate investigation for underlying disorders of hemostasis in women with excessive menstrual bleeding. Fertil Steril 2005; 84: 1345-51.
Statement 5 Female hormone testing (estradiol, progesterone, LH, FSH) should not be routinely done on women with HMB. Thyroid screening should only be obtained in the presence of signs and/or symptoms of thyroid disease. 3 III, C Supporting Statements: Epidemiological studies have found no link between hormone levels and heavy menstrual bleeding.1-2 One case–control study (n = 428) found no link between thyroid disorders and menstrual disturbances. Of the 214 women with thyroid disorders, 168 (78.5%) had regular menstrual cycles and 46 (21.5%) had irregular cycles. Out of 214 normal controls, matched for age and weight, 196 (91.6%) had normal menstruation and 18 (8.4%) had irregular cycles.3 Wd"
References 1. Eldred JM, Thomas EJ. Pituitary and ovarian hormone levels in unexplained menorrhagia. Obstetrics and Gynecology 1994;84(5): 775–8. 2. Haynes PJ, Anderson ABM, Turnbull AC. Patterns of menstrual blood loss in menorrhagia. Research and Clinical Forums 1979;1(2): 73–8. 3. Krassas GE, Pontikides N, Kaltsas T, et al. Menstrual disturbances in thyrotoxicosis. Clinical Endocrinology 1994;40(5):641–4.
Statement 6 Pregnancy test should be done in women of reproductive-age group. (III, C) Supporting Statements: Pregnancy is the primary consideration of abnormal uterine bleeding in women of childbearing age.1 Possible causes of pregnancy-related bleeding include abortion, ectopic pregnancy, placenta previa, abruptio placenta, and trophoblastic disease.2 A bimanual pelvic exam (to assess uterine size), beta-hCG test and pelvic ultrasound are useful in ruling out pregnancy-related causes. References 1. Shwayder JM. Pathophysiology of abnormal uterine bleeding. Obstet Gynecol Clin North Am 2000;27:219-34. 2. Albers JR, Hull SK, Wesley RM. Abnorma uterine bleeding. Am Acad Fam Physician 2004.
Statement 7 Ultrasound is the first-line diagnostic tool abnormalities. (I, A)
for identifying
structural
Supporting Statements: Transvaginal ultrasound (TVUS) may reveal myomas, endometrial thickening, or focal masses. It is highly sensitive for detecting endometrial carcinoma (96%) and endometrial abnormality (92%).1 TVUS is most sensitive in detecting disease in women with postmenopausal bleeding, since a cutoff of 5 mm or less reliably excludes endometrial cancer. Evidence suggests that measurement of endometrial thickness via TVUS can accurately discriminate between women at high and low risk of endometrial cancer. In a meta-analysis of > 6,000 women with postmenopausal bleeding, the use of a 5 mm cut-off to define abnormal endometrium identified 96% of women with endometrial cancer and 92% of women with any endometrial pathology with a false-positive rate of 39% and 10%, respectively.2 In premenopausal women, endometrial thickness varies between the proliferative phase (4 to 8 mm) and the secretory phase (8 to 14 mm), and TVUS should be scheduled between days 4 to 6 of the menstrual cycle, when the endometrium is the thinnest. Transvaginal ultrasound allows rapid assessment of size, position, and presence of uterine fibroids. The texture of the endometrium can be evaluated for homogeneity or heterogeneity. Adnexal pathology and pelvic tenderness can be assessed. Measurement of the endometrial echo in postmenopausal women is helpful in determining whether endometrial biopsy or further imaging studies are necessary. Normally, the endometrial echo measures less than 5 mm. Increased endometrial thickness is associated with intrauterine synechiae, endometrial hyperplasia, endometrial polyps, fibroids, and endometrial cancer. When the endometrium is We"
greater than 5 mm, cannot be visualized completely, is indistinct or indeterminate, an enhanced view is required with saline infusion sonography (SIS) or hysteroscopy. An endometrial echo of less than 5 mm is associated with malignancy in less than 0.5% of cases.3 A systematic review studied the use of ultrasound, sonohysteroscopy and hysteroscopy in an AUB population. The review showed a wide range in variation of results. For identification of any intrauterine pathology, transvaginal ultrasound (TVS) (10 studies) had a sensitivity range of 48–100% and specificity of 12–100%. For sonohysteroscopy (11 studies) the range of sensitivity was 85–100% and for specificity it was 50–100%. For hysteroscopy (3 studies) the range of sensitivity was 90–97% and for specificity it was 62–93%. The review concluded that all three methods were at least moderately accurate at identifying uterine pathology.4 A second review also showed a range of results for the various investigations.5 References 1. Tabor A, Watt HC, Wald NJ. Endometrial thickness as a test for endometrial cancer in women with post menopausal vaginal bleeding. Obstet Gynecol 2002;99:663-70. 2. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al: Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 1998;20:1510–1517. 3. Weber A, Belinson JL, Bradley LD, et al: Vaginal ultrasonography versus endometrial biopsy in women with postmenopausal bleeding. Am J Obstet Gynecol. 1997;177:924–929. 4. Farquhar C, Ekeroma A, Furness S, et al. A systematic review of transvaginal ultrasonography, sonohysterography and hysteroscopy for the investigation of abnormal uterine bleeding in premenopausal women. Acta Obstetricia et Gynecologica Scandinavica 2003;82(6):493–504. 5. Dueholm M, Lundorf E, Olesen F. Imaging techniques for evaluation of the uterine cavity and endometrium in premenopausal patients before minimally invasive surgery. Obstetrical and Gynecological Survey 2002;57(6):389–403.
Statement 8 Saline-infusion sonography should not be used as first-line diagnostic tool, but may be useful in providing a more accurate evaluation of the uterus with intracavitary lesions. (I, A) Supporting Statements: Saline infusion sonography infuses saline into the endometrial cavity during TVUS to enhance the image. Confirmation of an intracavitary mass (submucous fibroid or polyp) is improved substantially with SIS.1-2 A meta-analysis involving 16 studies on saline contrast hysterosonography for AUB showed pooled sensitivity of 95% and specificity of 88%. The review concluded that saline infusion sonography was an accurate method for investigation of uterine pathology.3 However, it should not be used as first-line in the investigation of AUB.4 References 1. Justin Clark T. Outpatient hysteroscopy and ultrasonography in the management of endometrial disease. Curr Opin Obstet Gynecol 2004; 16: 305–311. 2. Widrich T, Bradley L, Mitchinson AR, et al: Comparison of saline infusion sonography with office hysteroscopy for the evaluation of the endometrium. Am J Obstet Gynecol 1996;174:1327–1334. 3. De Kroon CD, de Bock GH, Dieben SW, et al. Saline contrast hysterosonography in abnormal uterine bleeding: a systematic review and meta-analysis. BJOG: an International Journal of Obstetrics and Gynaecology 2003; 110:(10)938–47.
Wf"
4.
National Collaborating Centre for Women’s and Children’s Health; National Institute for Health and Clinical Excellence. Heavy menstrual bleeding. Clinical guideline. 24 January 2007. London: RCOG Press, 2007.
Statement 9 Hysteroscopy should be used as a diagnostic tool only when ultrasound results are inconclusive, e.g. to determine the exact location of a fibroid or the exact nature of an abnormality. (I, A) Supporting Statements: Modern hysteroscopes combine miniaturization with excellent image resolution and visualization.1 It is better at identifying polyps than ultrasound.2 Hysteroscopy allows direct visualization of the endometrial cavity and, importantly, targeted endometrial sampling of any suspicious areas. A review of 65 papers on the use of hysteroscopy in endometrial disease found that hysteroscopy is accurate at identifying endometrial cancer (sensitivity = 86.4%, specificity = 99.2%), but less so at identifying endometrial disease (sensitivity = 78%, specificity = 95.8%).3 References 1. Fraser IS. Menorrhagia – a pragmatic approach to the understanding of causes and the need for investigations. Br J Obstet Gynaecol 1994; 101(supplement 11): 3–7. 2. National Collaborating Centre for Women’s and Children’s Health; National Institute for Health and Clinical Excellence. Heavy menstrual bleeding. Clinical guideline. 24 January 2007. London: RCOG Press, 2007. 3. Clark TJ, Voit D, Gupta JK, et al. Accuracy of hysteroscopy in the diagnosis of endometrial cancer and hyperplasia: a systematic quantitative review. JAMA: the Journal of the American Medical Association 2002;288(13):1610–21.
Statement 10 Endometrial biopsy may be performed in symptomatic women who are at high risk for the disease. Endometrial sampling is recommended for: 1 1. Any postmenopausal woman with bleeding or premenopausal woman with heavy and/ or irregular vaginal bleeding; 2. Postmenopausal women with endometrial cells seen on pap smear or premenopausal women with atypical glandular cells on pap smear; 3. Breast cancer patients on Tamoxifen who complain of abnormal vaginal bleeding; and 4. Women who are still “menstruating” after 52 years of age Reference 1. Society of Gynecologic Oncologists of the Philippines. General Guidelines for the General Obstetrician and Gynecologist: SGOP, 2003.
V. MANAGEMENT A. Medical Management of Acute Heavy Menstrual Bleeding 1. High dose estrogen 2. High dose combined oral contraceptives 3. Progestins 4. Tranexamic acid WM"
Statement 1 Medical management of non-gestational acute AUB should be considered before any surgical procedure, unless bleeding is suspected to be due to intrauterine lesions (i.e. submucous myoma).1 (III, C) Reference 1. Munro MG. Acute uterine bleeding unrelated to pregnancy. Gynaecol Forum 2007;12 (2):1114.
Statement 2 High dose conjugated equine estrogen is effective in treating acute severe abnormal uterine bleeding. (I, A) Supporting Statements: One randomized trial showed that intravenous conjugated equine estrogen (CEE) was effective in treating non-pregnant acute uterine bleeding.1 In this study, 25 mg intravenous CEE every 4 hours stopped the bleeding within 5 hours in 72% of the treatment group versus 38% of the placebo group. In another review, oral CEE 2.5 mg every 6 hours was recommended as outpatient management of severe acute bleeding in the non-pregnant woman.2 Promethazine was given as needed for nausea. Such regimen is continued for 24 hours, to achieve hemodynamic stability. References 1. DeVore GR, Owens O, Kase N. Use of intravenous Premarin in the treatment of dysfunctional uterine bleeding- a double-blind randomized control study. Obstet Gynecol 1982;59:285-91. 2. Ely JW, et al. Abnormal uterine bleeding: a management algorithm. J Am Board Fam Med 2006;19:590-602.
Statement 3 Combined oral contraceptive pills may be used to treat acute AUB. (I, B) Supporting Statements: Combined oral contraceptives (COCs) are frequently used in treating acute AUB despite the relative lack of evidence. In a modest-sized randomized controlled trial, COC containing 35 ug ethinylestradiol and 1 mg norethisterone was equivalent to a progesterone-only regimen; bleeding stopped within 3 days when the COC was given 3 times a day for a week and then tapered to once a day for 3 weeks.1 In the algorithm for treating acute AUB, a tapering schedule of COCs was recommended.2 The regimen is 30 ug ethinylestradiol/norgestrel 0.3 mg 1 active pill 4 times a day for 4 days, followed by 3 times daily for 3 days, then 2 times a day for 2 days, then once daily for 3 weeks. References 1. Munro MG, Mainor N, Basu R, et al. Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: a randomized trial. Obstet Gynecol 2006;108:924-9. 2. Ely JW, et al. Abnormal uterine bleeding: a management algorithm. J Am Board Fam Med 2006;19:590-602.
Statement 4 There is limited evidence that oral progestogens are effective in treating acute, L!"
heavy menstrual bleeding. (II, B) Supporting Statements: In one study (24 adolescents hospitalized for excessive bleeding and anemia), oral medroxyprogesterone acetate (MPA) was given at a dose of 60-100 mg for the first day and 20 mg/day for the next 10 days.1 This resulted to a reduction in blood loss in all patients (25% stopped bleeding within 24 hours, the rest by the fourth day). In an RCT, 60 mg /day for a week, followed by 20 mg/day, stopped bleeding on average on day 3 of the regimen.2 Norethisterone acetate (5-15 mg/day) daily until cessation of bleeding for at least 2 days, followed by 5-10 mg/day for 3-6 weeks, is another alterntive.3 References 1. Aksu F, Madazli R, Budak E, et al. High-dose medroxyprogesterone acetate for the treatment of dysfunctional uterine bleeding in 24 adolescents. Aust NZ J Obstet Gynaecol 1997;37:22831. 2. Munro MG, Mainor N, Basu R, et al. Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: a randomized trial. Obstet Gynecol 2006;108:924-9. 3. Munro MG. Acute uterine bleeding unrelated to pregnancy. Gynaecol Forum 2007;12 (2):1114.
Statement 5 Tranexamic acid may be used to treat of acute AUB. (I, A) Supporting Statements: In one study, menorrhagia treatment for five days from day 1 of menses during three consecutive menstrual periods was done on 76 patients. Twenty-seven (27) patients were randomised to take ethamsylate 500 mg six hourly, 23 patients to take mefenamic acid 500 mg eight hourly, and 26 patients to take tranexamic acid 1 g six hourly. Ethamsylate did not reduce mean menstrual blood loss whereas mefenamic acid reduced blood loss by 20% (mean blood loss 186 ml before treatment, 148 ml during treatment) and tranexamic acid reduced blood loss by 54% (mean blood loss 164 ml before treatment, 75 ml during treatment). Sanitary towel usage was significantly reduced in patients treated with mefenamic acid and tranexamic acid. Tranexamic acid given during menstruation is a safe and highly effective treatment for excessive bleeding. Reference 1. Bonnar J & Sheppard BL. Treatment of menorrhagia during menstruation: randomised controlled trial of ethamsylate, mefenamic acid and tranexamic acid. BMJ 1996;313:579-582.
B. Medical Management of Chronic Heavy Menstrual Bleeding 1. Levonorgestrel-releasing intrauterine system (LNG-IUS) 2. Antifibrinolytic agents (AFA) 3. Nonsteroidal anti-inflammatory drugs (NSAIDs) 4. Combined oral contraceptives 5. Cyclic progestogen 6. Danazol
LW"
Statement 1 The Levonorgestrel-releasing intrauterine system (LNG IUS) is a highly effective treatment for heavy menstrual bleeding, with the additional benefit of relieving dysmenorrhea. (I, A) Supporting Statements: The levonorgestrel-releasing intrauterine system (LNG-IUS) is a highly effective, reversible contraceptive with the additional benefits of reducing blood loss and dysmenorrhea. The LNG-IUS reduces endometrial thickness and vascularity, leading to a marked reduction in blood loss. Recent evidence shows that LNG-IUS normalizes blood flow in women with heavy menstrual bleeding, with 35% being amenorrheic at 2 years (Busfield et al, 2006). A meta-analysis of 9 RCTs comparing progesterone releasing IUS with cyclic oral norethisterone (days 5-26 of cycle) showed that the IUS was significantly more effective in reducing blood loss. Women with an LNG IUS are more satisfied and willing to continue with treatment but experience more side effects, such as intermenstrual bleeding and breast tenderness. When compared with endometrial ablation, the LNG IUS results in a lesser reduction in menstrual blood loss but there is no evidence of a difference in the rate of satisfaction with treatment. In one trial of women awaiting hysterectomy, where the LNG IUS was compared with a control group taking their existing medical therapy, a higher proportion of the women in the intrauterine device group cancelled their planned surgery after six months of treatment. References: 1. Busfield RA, Farquhar CM, Sowter MC, et al. A randomized trial comparing the levonorgestel intrauterine system and thermal balloon ablation for heavy menstrual bleeding. Br J Obstet Gynaecol 2006; 113:257-63. 2. Lethaby A, Cooke I, Rees MC. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2005, Issue 4.
Statement 2 Antifibrinolytic therapy causes a greater reduction in heavy menstrual bleeding when compared with placebo or other medical treatments (NSAIDs, oral luteal progestogens and ethamsylate). This treatment is not associated with an increase in side effects compared to placebo or other medical therapies (NSAIDs, oral luteal progestogens, ethamsylate). (I, A) Supporting Statements: Antifibrinolytic agents inhibit plasminogen activation and subsequently fibrinolysis. An increase in the levels of plasminogen activators has been found in the endometrium of women with heavy menstrual bleeding compared with those with normal menstrual loss. A meta-analysis of four randomized controlled trials compared antifibrinolytic agents versus placebo or other medical therapies (NSAIDs, oral luteal progestogen and ethamsylate). Results showed a significant reduction in mean blood loss with antifibrinolytic therapy compared to placebo (WMD -94.0, 95% CI -151.4 to -36.5). In all studies comparing antifibrinolytics with mefenamic acid, luteal norethisterone and ethamsylate, results showed a significant reduction in mean blood LL"
loss (WMD -73.0, 95% CI -123.4 to -22.6; WMD -111.0, 95% CI -178.5 to -43.5; and WMD -100, 95% CI -143.9 to -56.1, respectively) and a strong, although nonsignificant trend in favor of tranexamic acid in the participants’ perception of an improvement in menstrual blood loss. Moreover, there was no associated increase in side effects compared to placebo and other medical therapies. Reference: 1. Lethaby A, Farquhar C, Cooke I. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2000, Issue 4.
Statement 3 Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce heavy menstrual bleeding when compared with placebo, but are less effective than tranexamic acid, danazol, or levonorgestrel-releasing intrauterine system (LNG-IUS). Limited evidence shows no significant difference in efficacy between NSAIDs and oral luteal progestogen, ethamsylate, or oral contraceptive pill. (I, A) Supporting Statements: A rationale for the use of nonsteroidal anti-inflammatory drugs is due to an accumulation of data suggesting a role for prostaglandins in the pathogenesis of HMB (Hagenfeldt 1987). The endometrium of women with excessive menstrual bleeding has been found to have higher levels of prostaglandin E2 and prostaglandin F2a when compared with women with normal menses; using an NSAID may reduce prostaglandin production by inhibiting the enzyme cyclo-oxygenase. In the latest Cochrane review of nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding, seventeen randomized controlled trials comparing individual NSAIDs with each other, placebo or other medical treatments in women with heavy menstrual bleeding were analyzed. Seven crossover trials were also described. Results showed that NSAIDs were more effective than placebo, but less effective than tranexamic acid, danazol, LNG-IUS, in reducing heavy menstrual bleeding. In a limited number of studies with small sample sizes, there were no statistically significant differences between NSAIDs and other medical treatments like oral luteal progestogen, ethamsylate, and oral contraceptive. Lastly, there was no difference in efficacy between different NSAIDs (naproxen and mefenamic acid) in reducing heavy menstrual bleeding. References: 1. Hagenfeldt K. The role of prostaglandins and allied substances in uterine haemostasis. Contraception 1987;36(1):23–35. 2. Lethaby A, Augood C, Duckitt K, Farquhar C. Nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2007, Issue 4.
Statement 4 Combined oral contraceptives may be an alternative in the medical management of heavy menstrual bleeding. There was no significant difference in menstrual blood loss (MBL) between treatments with OCP, danazol, and NSAIDs. (I, B) Supporting Statements: A Cochrane database systematic review found only one small (45 patients) randomized, cross-over trial investigating the combined oral contraceptive in the L]"
treatment of heavy menstrual bleeding (Frasier 1991). Treatments given were mefenamic acid, naproxen, low dose danazol and a combined oral monophasic contraceptive pill. There was no significant difference in menstrual blood loss reduction between those patients treated with the OCP and danazol, mefenamic acid or naproxen. References: 1. Iyer V, Farquhar C, Jepson RG. Oral contraceptive pills for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 1997, Issue 2. 2. Frasier IS, McCarron G. Randomized trial of 2 hormonal and 2 prostaglandin inhibiting agents in women with a complaint of menorrhagia. Aust NZ J Obstet Gynaecol 1991; 31: 66-70.
Statement 5 Cyclic progestogen given for twenty one (21) days for ovulatory bleeding results in a significant reduction in blood loss, although it has no advantage over other medical therapies (NSAIDs, tranexamic acid, danazol, and IUS). (I, A) Supporting Statements: A meta-analysis of seven randomized controlled trials compared cyclic progestogen with other medical therapies such as danazol, tranexamic acid, non-steroidal antiinflammatory drugs (NSAIDs) and the IUS. Progestogens administered from day 15 or 19 to day 26 of the cycle offer no advantage over other medical therapies in the treatment of menorrhagia in women with ovulatory cycles. Progestogen therapy for 21 days of the cycle results in a significant reduction in menstrual blood loss, although women found the treatment less acceptable than intrauterine levonorgestrel. This regimen of progestogen may have a role in the short-term treatment of menorrhagia. Reference: 1. Lethaby A, Irvine GA, Cameron IT. Cyclical progestogens for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2008, Issue 1.
Statement 6 Danazol appears to be an effective treatment for heavy menstrual bleeding compared to other medical treatments. However, danazol use may be limited by its side effect profile, its acceptability to women and the need for continuing treatment. (I, A) Supporting Statements: Danazol appears to be more effective than placebo, progestogens, NSAIDs and the OCP at reducing MBL. This is based on nine randomized controlled trials (353 women), but majority of which are unsuitable for meta-analysis. Results are based on a small number of trials, all of which are underpowered, and with wide confidence intervals. Treatment with Danazol caused more adverse events than NSAIDs (OR 7.0; 95% CI 1.7 to 28.2) and progestogens (OR 4.05, 95% CI 1.6 to10.2). The small number of trials, and the small sample sizes of the included trials limit the recommendations for clinical care. Further studies are unlikely in the future and this review will not be updated unless further studies are identified. Reference: 1. Beaumont HH, Augood C, Duckitt K, Lethaby A. Danazol for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2007, Issue 3.
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! C. Surgical Management of Heavy Menstrual Bleeding 1. Dilatation and curettage 2. Endometrial ablation 3. Hysterectomy Statement 1 Dilatation and curettage should not be used as a therapeutic treatment. (III, C) Supporting Statements: The observational study (n = 22) showed that MBL was reduced for 1 month after dilatation and curettage but then returned to previous levels.1 There were no systematic reviews or RCTs. Reference: 1. Haynes PJ, Hodgson H, Anderson AB, et al. Measurement of menstrual blood loss in patients complaining of menorrhagia. British Journal of Obstetrics and Gynaecology 1977; 84(10):763–8.
Statement 2 Dilatation and curettage may be performed for acute heavy mesntrual bleeding unresponsive to initial medical management. (III, C) Reference: 1. Ely JW. Journal of American Board of Family Medicine. 2007.
Statement 3 Endometrial ablation may be offered as an initial treatment for heavy menstrual bleeding. It should be considered in women who have a normal uterus and also those with small uterine fibroids (less than 3 cm in diameter). In women with heavy menstrual bleeding alone, with uterus no bigger than a 10-week pregnancy, endometrial ablation should be considered preferable to hysterectomy. Second-generation ablation techniques should be used where no structural or histological abnormality is present. [I, A] Supporting Statements: Three reviews and one RCT show that endometrial ablation and resection methods produce clinically relevant reductions in MBL and are associated with improvements in quality of life. Transcervical resection of the endometrium (TCRE), microwave endometrial ablation (MEA), thermal balloon endometrial ablation (TBEA) and rollerball endometrial ablation (REA) techniques appear to be largely equivalent to one another in terms of clinical outcome, although one RCT found that MEA is superior to TCRE in terms of satisfaction at 5 years follow-up. Endometrial ablation and resection techniques are marginally less effective than hysterectomy at improving MBL and quality of life. Inclusion criteria of RCTs showed that uterine fibroids < 3 cm in size were allowable.. When compared with hysterectomy, both TBEA and Lg"
MEA are less costly, but result in slightly fewer QALYs. MEA performed in an outpatient setting under local anaesthetic compares favourably in terms of cost with standard MEA in a day-case setting after drug preparation of the endometrium. Endometrial ablation versus other treatments Hysterectomy was compared with endometrial ablation in a systematic review. Hysterectomy provided greater reductions in MBL.(at 12 months (three studies, n = 440) OR 0.12 [95% CI 0.06 to 0.25]). More patients favored hysterectomy (at 12 months (three studies, n = 519) OR 0.46 [95% CI 0.24 to 0.88] and at 24 months (three studies, n = 354) OR 0.31 [95% CI 0.16 to 0.59]). Quality of life measures SF36) showed no difference between groups. Endometrial ablation techniques required less time to undertake ((five studies, n = 706) WMD = "23.06 [95% CI "23.80 to "22.32] in favor of ablation/resection), shorter hospital stays ((five studies, n = 706) WMD = "4.91 [95% CI "4.95 to "4.87]) and fewer adverse events. Of the 13 types of adverse event reported, results favored ablation/resection over hysterectomy for eight of these, and five were no different. However, more women in the endometrial ablation groups required further surgery within 12 months ((five studies, n = 706) OR 7.33 [95% CI 4.18 to 12.86]). It was concluded that ablation/resection is an alternative to hysterectomy. Ablation/resection is less effective at reducing MBL and improving satisfaction. Ablation/resection, however, leads to shorter surgery, shorter hospital stay and fewer complications.1 Endometrial ablation/resection There is one systematic review which examined the effectiveness and safety of MEA and TBEA for DUB. Amenorrhea rates at 12 months reported by seven trials ranged from 36% to 40% for MEA and from 10% to 40% for TBEA. The review also reported significant reductions in levels of MBL or reclassification of bleeding patterns for both MEA and TBEA. There were high levels of satisfaction (> 75%) for both MEA and TBEA. The review concluded that both MEA and TBEA were equivalent to first-generation ablation techniques.2 A second systematic review (19 RCTs) compared the various ablation techniques with one another for treatment of DUB. Only limited differences were found when comparing one ablation method with another.3 Laser ablation versus TCRE There were two RCTs (n = 388) were identified. There was no difference between laser ablation and TRCE for amenorrhea rates, satisfaction, HRQoL or complications. Vaporizing electrode ablation versus TCRE One RCT (n = 91) was identified. There were no differences between methods for amenorrhea rates, satisfaction or HRQoL. REA versus TCRE There was no difference between techniques in terms of future hysterectomy or resurgery at 2 and 5 years follow-up. Thermal laser ablation versus TCRE One RCT (n = 111) was identified. There were no differences between groups for menorrhagia, re-surgery, complications or satisfaction. Hydrothermablation versus REA Ld"
One RCT (n = 269) was identified. Hydrothermablation patients were more likely to have local than general anesthesia (OR 2.9 [95% CI = 1.6 to 5.1]) and were less likely to experience hematometra (OR 0.18 [95% CI 0.03 to 0.93]) but were more likely to have abdominal pain (OR 1.9 [95% CI 1.1 to 3.1]) and nausea (OR 3.7 [95% CI 1.5 to 9.0]). Cryoablation versus REA Two RCTs (n = 279) were identified. Women in the cryoablation group were less likely to have amenorrhea at 1 year (OR 0.3 [95% CI 0.2 to 0.6]) but more likely to have local than general anesthesia (OR 13.2 [95% CI 5.8 to 30.0]). There were no differences in satisfaction rates, success rates (PBAC < 75), menorrhagia rates or hysterectomy rates. Electrode ablation (balloon or mesh) versus TCRE Two RCTs (n = 520) were identified. The operation time with TCRE was longer (WMD 18.7 minutes [95% CI 16.8 to 20.7]). The electrode group was more likely to have local than general anesthesia (OR 15.9 [95% CI 10.1 to 25.1] and less likely to have cervical tears or lacerations (OR 0.11 [95% CI "0.01 to 0.90]). There were no differences between groups in amenorrhea rates, complications rates, 12 month PBAC, satisfaction rates or need for hysterectomy. MEA versus TCRE plus REA One RCT (n = 322) was identified. At 2 years follow-up, microwave was more satisfactory and acceptable than TCRE (OR 1.9 [95% CI 1.1 to 3.3] and OR 2.7 [1.1 to 6.8], respectively). At 5 years follow-up the difference was maintained (OR 2.3 [95% CI 1.2 to 4.3] and OR 3.7 [95% CI 1.3 to 10.1], respectively). The hysterectomy rate was significantly lower (18% versus 28%) following MEA. In addition, odds of hemorrhage were lower in the microwave group (OR 0.14 [95% CI 0.02 to 0.80]). However, equipment failure rates (OR 4.07 [95% CI 1.1 to 15.0]), vomiting (OR 4.0 [95% CI 1.4 to 11.7] and uterine cramping (OR 1.7 [95% CI 1.1 to 2.8]) were greater in the MEA group. There were no differences in other outcomes or in the same outcomes at different time periods. TBEA versus REA One RCT (n = 239) was identified. Amenorrhea was less likely with TBEA at 12 and 36 months (OR 0.60 [95% CI 0.33 to 0.96] and OR 0.50 [95% CI 0.25 to 0.97], respectively) but there were no differences at 24 months and 5 years. At 5 years, odds of satisfaction with treatment were lower in the balloon group (OR 0.13 [95% CI 0.02 to 0.94]), and complications were more likely with TBEA than with REA. Duration of surgery was lower in the balloon group (WMD 20.8 minutes [95% CI 19.2 to 22.5]). Other outcomes showed no differences at 12, 24 and 36 months. TBEA versus TCRE One RCT (n = 82) was identified. TBEA was quicker (WMD 13 minutes [95% CI 10.8 to 15.2), mean intra-operative blood loss was lower (WMD "81.8 ml [95% CI "70.3 to "93.3]) and satisfaction was greater at 24 months (OR 7.2 [95% CI 1.4 to 35.9]) when compared with TCRE. TBEA versus laser ablation One RCT (n = 70) was identified. Women having TBEA treatment had a significantly greater pain score than women in the laser group (WMD 32.7 [95% CI 23.7 to 41.7]). Le"
At 12 months follow up, women in the TBEA group had higher scores on the Euroquol 5D VAS than women in the laser group (WMD 5.3 [95% CI 0.11 to 10.6]). Bipolar radiofrequency endometrial ablation versus TBEA One RCT (n = 126) was identified. Amenorrhea was more likely in the bipolar radiofrequency group (OR 7.4 [95% CI 3.8 to 14.4]) and women in the bipolar radiofrequency group were more likely to be satisfied with treatment outcome at 12 months (OR 3.0 [95% CI 1.3 to 7.0]). References: 1. Lethaby A, Shepperd S, Cooke I, Farquhar C. Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding.(Cochrane Review). In: Cochrane Database of Systematic Reviews, Issue 2, 2004. Oxford: Update Software. 2. Garside R, Stein K, Wyatt K, et al. The effectiveness and cost-effectiveness of microwave and thermal balloon endometrial ablation for heavy menstrual bleeding: a systematic review and economic modelling. Health Technology Assessment 2004;8(3):iii,1–155. 3. Lethaby A, Hickey M. Endometrial destruction techniques for heavy menstrual bleeding. (Cochrane Review). In: Cochrane Database of Systematic Reviews, Issue Oxford, 2005. Oxford: Update Software.
Statement 4 Hysterectomy should not be used as first-line treatment for heavy menstrual bleeding. (I, C) Supporting evidence: In one systematic review (n = 821) in 2006, eight RCTs compared pharmaceutical with surgical treatments for HMB. Two RCTs in the systematic review examined use of pharmaceutical or surgical interventions on women with HMB in a secondary care setting. The difference between pharmaceutical treatments and surgery diminished over time. There was no statistical difference between the groups by the 5th year of follow-up. Regarding control of bleeding, (cure or improvement): at 4 months (n = 186) OR 10.6 (95% CI 5.3 to 21.3) in favor of surgery, by 2 years (n = 173) OR 2.39 (95% CI 1.21 to 4.70) in favor of surgery, and by 5 years (n = 140) OR 1.99 [95% CI 0.84 to 4.73] There was no statistical difference between the groups. The figures for patient satisfaction were: at 4 months (n = 183) OR 8.28 (95% CI 4.29 to 15.97) in favor of surgery, by 2 years (n = 173) OR 2.83 [95% CI 1.46 to 5.50] in favor of surgery, and by 5 years (n = 140) OR 1.69 (95% CI 0.77 to 3.70) with no statistical difference between the groups. However, women in the pharmaceutical group were more likely to undergo additional surgery: by 2 years follow-up (n = 236) OR 0.12 (95% CI 0.06 to 0.22) in favour of surgery and by 5 years follow-up (n = 140) OR 0.11 (95% CI 0.06 to 0.22) in favor of surgery.1 Six other RCTs compared LNG-IUS with surgery (hysterectomy, ablation) in secondary care settings. These studies concluded that the treatments were equivalent. The figures showed that objective measurement of MBL at 12 months was in favor of surgery (one RCT, n = 223, OR 25.7 [95% CI 1.5 to 440.0]). Also, the subjective measurement of MBL at 12 months was in favor of surgery (three RCTs, n = 189, OR 3.99 [95% CI 1.53 to 10.38]).However, results from health related quality of life (HRQoL) measures were more mixed. There was no difference between groups on the SF-36 (a short form with 36 questions, used in determining health status of patients) scale for general health, physical function, mental health, vitality and physical role limitation. There were statistically significant differences for emotional role (n = 269, Lf"
WMD 9.67 [95% CI 1.65 to 17.69]), social function (n = 274, WMD 3.64 [95% CI "1.14 to 8.43]) and bodily pain (n = 274, WMD 6.98[95% CI 1.68 to 12.29]) in favor of surgery. Use of LNG-IUS was more likely to result in additional surgery at 12 months (n = 423, OR 0.11 [95% CI 0.04 to 0.30]) and were less likely to have reported adverse effects (OR 0.24 [95% CI 0.11 to 0.49]).1 While surgery has an advantage over pharmaceutical treatment in terms of outcome, this does not take into account the reversible nature of pharmaceutical treatment compared with surgery. The systematic review states that investigations for causes of HMB, attempts at pharmaceutical treatment and provision of full information to the woman are required prior to hysterectomy.2 A consensus statement highlights that hysterectomy for HMB should only be undertaken after investigations to establish cause of HMB, failed pharmaceutical treatment and full information provision to the woman.3 In addition, hysterectomy is only indicated where HMB is causing anemia and/or serious HRQoL impact. Patient preference studies show that women want certain outcomes for treatment of HMB, but also often want to avoid hysterectomy in order to achieve these outcomes.4-8 References 1. Marjoribanks J, Lethaby A, Farquhar C. Surgery versus medical therapy for heavy menstrual bleeding. (Cochrane Review). In: Cochrane Database of Systematic Reviews, Issue 2, 2006. Oxford: Update Software. 2. Lefebvre G, Allaire C, Jeffrey J, et al. SOGC clinical guidelines. Hysterectomy [French]. Journal of Obstetrics and Gynaecology Canada: JOGC 2002;24(1):37–61. 3. Schilling J, Wyss P, Faisst K, et al. Swiss consensus guidelines for hysterectomy. Swiss Society of Gynecology and Obstetrics, Switzerland. International Journal of Gynaecology and Obstetrics 1999;64(3):297–305. 4. Bourdrez P, Bongers MY, Mol BW. Treatment of dysfunctional uterine bleeding: patient preferences for endometrial ablation, a levonorgestrel-releasing intrauterine device, or hysterectomy. Fertility and Sterility 2004; 82(1):160–6. 5. Nagele F, Rubinger T, Magos A. Why do women choose endometrial ablation rather than hysterectomy? Fertility and Sterility 1998;69(6):1063–6. 6. Sculpher MJ, Dwyer N, Browning J, et al. A survey of women’s preferences regarding alternative surgical treatments for menorrhagia. Health Expectations 1998;1(2):96–105. 7. Mingo C, Herman CJ, Jasperse M. Women’s stories: Ethnic variations in women’s attitudes and experiences of menopause, hysterectomy, and hormone replacement therapy. Journal of Womens Health and Gender-Based Medicine 2000;9(Suppl 2): S27–38. 8. Nathorst-Boos J, Fuchs T, von Schoultz B. Consumer’s attitude to hysterectomy: The experience of 678 women. Acta Obstetricia et Gynecologica Scandinavica 1992;71(3):230–4.
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APPENDIX A LEVELS OF EVIDENCE AND GRADES OF RECOMMENDATION LEVEL I II-1 II-2 II-3 III GRADE A B C D E GPP
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DEFINITION Evidence obtained from at least one properly randomized controlled trial Evidence obtained from well-designed controlled trials without randomization Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group Evidence obtained from multiple time series with or without the intervention. Opinions of respected authorities, based on clinical experience; descriptive studies and case reports or reports of expert committees. DEFINITION There is good evidence to support the recommendation of the practice in abnormal uterine bleeding. There is fair evidence to support the recommendation of the practice in abnormal uterine bleeding. There is insufficient evidence to recommend for or against the inclusion of the practice in abnormal uterine bleeding. There is fair evidence to support the recommendation that the practice be excluded in abnormal uterine bleeding. There is good evidence to support the recommendation that the practice be excluded in abnormal uterine bleeding. A good practice point (GPP) is a recommendation for best practice based on the experience of the Technical Working Group.
APPENDIX B DRUG DOSAGES 1. Levonorgestrel-releasing intrauterine system once every 5 years 2. Tranexamic acid 1 gram QID PO during heavy bleeding x 3 days 3. Ibuprofen 200 mg PO TID during heavy bleeding x 3 days 4. Mefenamic acid 500 mg PO TID during heavy bleeding x 3 days 5. Naproxen 550 mg LD, then 275 mg PO BID during heavy bleeding x 3 days 6. Medroxyprogesterone 10 mg PO OD on cycle days 16-25 for anovulatory cycles 7. Medroxyprogesterone 10 mg PO TID on cycle days 5-26 for ovulatory cycles 8. Norethisterone acetate 5 mg PO TID on cycle days 16-25 for anovulatory cycles 9. Norethisterone acetate 5 mg PO TID on cycle days 5-26 for ovulatory cycles 10. Danazol 200-400 mg PO daily for progestin-resistant cases
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