Diagnosis of Abnormal Uterine Bleeding in Reproductive-Aged Women.pdf

The American College of Obstetricians and Gynecologists P R AC T I C E BUL L E T I N WOMEN’S HEALTH CARE PHYSICIANS clin...

The American College of Obstetricians and Gynecologists P R AC T I C E BUL L E T I N WOMEN’S HEALTH CARE PHYSICIANS clinical management guidelines for obstetrician – gynecologists Number 128, July 2012 (Reaffirmed 2016) Diagnosis of Abnormal Uterine Bleeding in Reproductive-Aged Women Menstrual flow outside of normal volume, duration, regularity, or frequency is considered abnormal uterine bleeding (AUB). One third of outpatient visits to the gynecologist are for AUB, and it accounts for more than 70% of all gyne- cologic consults in the perimenopausal and postmenopausal years (1). Many new diagnostic modalities are available to assist the clinician in evaluating the woman with alterations in her normal menstrual patterns. The purpose of this document is to provide evidence-based management guidelines for the evaluation of the reproductive-aged patient with AUB. A secondary purpose is to introduce a new classification system for AUB. This document does not address pregnancy-related bleeding or postmenopausal bleeding. Background (polyp, adenomyosis, leiomyoma, malignancy and hyper- plasia, coagulopathy, ovulatory dysfunction, endometrial, Definition and Nomenclature iatrogenic, and not yet classified), known by the acronym The duration of normal menstrual flow is generally 5 days, PALM–COEIN, was introduced in 2011 by the Inter- and the normal menstrual cycle typically lasts between national Federation of Gynecology and Obstetrics (FIGO) 21 days and 35 days. Descriptive terms that traditionally (3). The American College of Obstetricians and Gyne- have been used to characterize abnormal menstrual bleed- cologists supports the adoption of the PALM–COEIN ing patterns include menorrhagia, metrorrhagia, poly- nomenclature system developed by FIGO to standardize menorrhea, and oligomenorrhea. Menorrhagia, or heavy the terminology used to describe AUB. menstrual bleeding, is defined as menstrual blood loss The PALM–COEIN system classifies uterine bleed- greater than 80 mL (2). However, this definition is used ing abnormalities by bleeding pattern as well as by for research purposes and, in practice, excessive blood loss etiology. The overarching term AUB is paired with des- should be based on the patient’s perception. Metrorrhagia criptive terms to denote bleeding patterns associated is defined as bleeding between periods. Polymenorrhea with AUB, such as heavy menstrual bleeding (instead is defined as bleeding that occurs more often than every of menorrhagia) and intermenstrual bleeding (instead of 21 days, and oligomenorrhea is defined as bleeding that metrorrhagia). Abnormal uterine bleeding is further clas- occurs less frequently than every 35 days. sified by one (or more) letter qualifiers that indicate its In an effort to create a universally accepted system of etiology or etiologies (Fig. 1). The term dysfunctional nomenclature to describe uterine bleeding abnormalities uterine bleeding––often used synonymously with AUB in reproductive-aged women, a new classification system in the literature to indicate AUB for which there was no Committee on Practice Bulletins—Gynecology. This Practice Bulletin was developed by the Committee on Practice Bulletins—Gynecology with the assistance of Micah J. Hill, DO, Eric D Levens, MD, and Alan H. DeCherney, MD. The information is designed to aid practitioners in making decisions about appropriate obstetric and gynecologic care. These guidelines should not be construed as dictating an exclusive course of treatment or procedure. Variations in practice may be warranted based on the needs of the individual patient, resources, and limitations unique to the institution or type of practice.  Abnormal Uterine Bleeding (AUB) Heavy menstrual bleeding (AUB/HMB) Intermenstrual bleeding (AUB/IMB) PALM: Structural Causes COEIN: Nonstructural Causes Polyp (AUB-P) Coagulopathy (AUB-C) Adenomyosis (AUB-A) Ovulatory dysfunction (AUB-O) Leiomyoma (AUB-L) Endometrial (AUB-E) Submucosal myoma (AUB-LSM) Iatrogenic (AUB-I) Other myoma (AUB-LO) Not yet classified (AUB-N) Malignancy & hyperplasia (AUB-M) Fig. 1. Basic PALM–COEIN classification system for the causes of abnormal uterine bleeding in nonpregnant women of reproductive age. This system, approved by the International Federation of Gynecology and Obstetrics, uses the term AUB paired with descriptive terms that describe associated bleeding patterns (HMB or IMB), or a qualifying letter (or letters), or both to indicate its etiology (or etiologies). Modified from Munro MG, Critchley HO, Broder MS, Fraser IS. FIGO classification system (PALM–COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. FIGO Working Group on Menstrual Disorders. Int J Gynaecol Obstet 2011;113:3–13. [PubMed] [Full Text] ^ systemic or locally definable structural cause––is not part Diagnosis of the PALM–COEIN system, and discontinuation of its The evaluation of women with AUB includes a thorough use is recommended (3). medical history and physical examination, appropriate laboratory and imaging tests, and consideration of age- Pathophysiology related factors (see the section “Age-Based Common The most common causes of abnormal uterine bleeding Differential Diagnosis”). include uterine pathologies (PALM–COEIN classifica- tions are shown parenthetically), such as endometrial Medical History and Physical Examination polyps (AUB-P), adenomyosis (AUB-A), uterine leiomyo- mas (AUB-L), and endometrial hyperplasia or carcinoma A medical history should include questions about men- (AUB-M). Other possible etiologies include systemic strual bleeding patterns, severity and pain associated conditions, such as coagulopathies, both inherited (eg, with bleeding, and family history of AUB or other bleed- von Willebrand disease) and acquired (AUB-C), and ovul- ing problems because up to 20% of women (at any age) atory dysfunction (AUB-O). Ovulatory AUB is more presenting with heavy menstrual bleeding will have an common than AUB that is related to ovulatory dysfunc- underlying bleeding disorder (10–13). An initial screen- tion (4). ing for an underlying disorder of hemostasis should be Ovulatory dysfunction (AUB-O) is a spectrum of performed (see Box 1). If a concern remains about a pos- disorders that range from amenorrhea to irregular heavy sible bleeding disorder, the National Heart, Lung, and menstrual periods. They are typically the result of an endo- Blood Institute management guidelines may be helpful crinopathy, such as polycystic ovary syndrome (PCOS). (http://www.nhlbi.nih.gov/guidelines/vwd/vwd.pdf) (14, In these cases of AUB, the mechanisms of abnormal 15). The patient medical history also should include bleeding are related to unopposed estrogen. In ovulatory questions about the use of medications or herbal rem- AUB the hypothalamic–pituitary–ovarian axis is intact edies that might cause AUB, such as warfarin, heparin, and steroid hormone profiles are normal. Once regular nonsteroidal antiinflammatory drugs, hormonal contra- menses has been established during adolescence, ovula- ceptives, ginkgo, ginseng, and motherwort (16, 17). tory AUB accounts for most cases (4). Mechanisms for General physical findings of note include excessive ovulatory AUB include abnormal prostaglandin synthe- weight, signs of PCOS (eg, hirsutism and acne), signs of sis and receptor upregulation (5–7), increased local fibri- thyroid disease (eg, thyroid nodule), and signs of insulin nolytic activity (8), and increased tissue plasminogen resistance (eg, acanthosis nigricans on the neck). Physical activator activity (9). examination findings suggestive of a bleeding disorder 2 Practice Bulletin No. 128  Box 1. Clinical Screening for an Underlying Box 2. Diagnostic Evaluation of Disorder of Hemostasis in the Patient With Abnormal Uterine Bleeding ^ Excessive Menstrual Bleeding ^ Medical History Initial screening for an underlying disorder of hemo- stasis in patients with excessive menstrual bleeding Age of menarche and menopause should be structured by medical history (positive screen Menstrual bleeding patterns comprises any of the following): * Severity of bleeding (clots or flooding) Heavy menstrual bleeding since menarche Pain (severity and treatment) One of the following: Medical conditions Postpartum hemorrhage Surgical history Surgery-related bleeding Bleeding associated with dental work Use of medications Symptoms and signs of possible hemostatic disorder Two or more of the following symptoms: Bruising one to two times per month Physical Examination Epistaxis one to two times per month General physical Frequent gum bleeding Pelvic Examination Family history of bleeding symptoms —External *Patients with a positive screen should be considered for further —Speculum with Pap test, if needed* evaluation, including consultation with a hematologist and testing of von Willebrand factor and ristocetin cofactor. —Bimanual Reprinted from Kouides PA, Conard J, Peyvandi F, Lukes A, Kadir R. Laboratory Tests Hemostasis and menstruation: appropriate investigation for under- lying disorders of hemostasis in women with excessive menstrual Pregnancy test (blood or urine) bleeding. Fertil Steril 2005;84(5):1345–51. [PubMed] [Full Text] Complete blood count Targeted screening for bleeding disorders (when indicated)† include petechiae, ecchymoses, skin pallor, or swollen Thyroid-stimulating hormone level joints, although absence of these signs does not exclude the possibility of an underlying bleeding condition (18– Chlamydia trachomatis 20). A pelvic examination also should be performed as Available Diagnostic or Imaging Tests (when indicated) part of the physical examination, and in adults, this should Saline infusion sonohysterography include speculum and bimanual examination. A speculum examination should be performed to assess for cervical Transvaginal ultrasonography or vaginal lesions, with appropriate tissue sampling when Magnetic resonance imaging abnormalities are noted. A bimanual examination should Hysteroscopy be performed to assess the size and contour of the uterus. Available Tissue Sampling Methods (when indicated) Laboratory Testing Office endometrial biopsy Laboratory assessment for AUB should include a preg- Hysteroscopy directed endometrial sampling (office nancy test, complete blood count (CBC); measurement or operating room) of thyroid-stimulating hormone (TSH) levels; and cervi- cal cancer screening. Testing for Chlamydia trachomatis *For the nonadolescent patient only. should be considered, especially in patients at high risk Including a coagulation panel for adolescents and adult patients † with suspected bleeding disorders. of infection (see Box 2). Ovulatory status usually can be determined by the presence of cyclic menses. A CBC will indicate whether the patient has anemia or thrombocytopenic bleeding. The onset of heavy men- bleeding disorder, laboratory testing is indicated. Initial ses at menarche is often the first sign of von Willebrand tests should include a CBC with platelets, prothrombin disease. In all adolescents with heavy menstrual bleeding time, and partial thromboplastin time (fibrinogen or and adult patients with a positive screening history for a thrombin time are optional); bleeding time is neither Practice Bul­le­tin No. 128 3 sensitive nor specific, and is not indicated (14). Depend- 40 Years to Menopause ing on the results of the initial tests, or if a patient’s In women aged 40 years to menopause, abnormal uterine medical history is suggestive of an underlying bleeding bleeding may be due to anovulatory bleeding, which condition, specific tests for von Willebrand disease or represents normal physiology in response to declining other coagulopathies may be indicated, including von ovarian function. It also may be due to endometrial Willebrand–ristocetin cofactor activity, von Willebrand hyperplasia or carcinoma, endometrial atrophy, and leio- factor antigen, and factor VIII (14, 20–23). myomas. Hypothyroidism and hyperthyroidism are associated with AUB, although hypothyroidism is more common (24). Subclinical hyperthyroidism may be associated with AUB. In a study of apparently euthyroid women, Clinical Considerations and those with heavy menstrual bleeding had significantly Recommendations decreased levels of TSH and increased levels of total tri- iodothyronine, free triiodothyronine, free thyroxine, and When is imaging indicated in reproductive- total thyroxine as compared with normally menstruating aged women? women (25). Screening for thyroid disease with TSH The literature is unclear as to when evaluation with level measurement in women with AUB is reasonable imaging is indicated. Any patient with an abnormal and inexpensive. physical examination, such as an enlarged or globular uterus on bimanual examination, should undergo trans- Imaging Techniques vaginal ultrasonography to evaluate for myomas and The primary imaging test of the uterus for the evaluation adenomyosis. When symptoms persist despite treatment of AUB is transvaginal ultrasonography. If transvaginal in the setting of a normal pelvic examination, further ultrasonographic images are not adequate or further evalu- evaluation is indicated with transvaginal ultrasonogra- ation of the cavity is necessary, then sonohysterography phy, or biopsy, or both, if not already performed (see (also called saline infusion sonohysterography) or hyster- Fig. 2). When there is clinical suspicion for endometrial oscopy (preferably in the office setting) is recommended polyps or submucosal leiomyomas, sonohysterography (26). Magnetic resonance imaging is not a primary imag- or hysteroscopy will enable better detection of lesions. ing modality for AUB. In adolescents, transabdominal The decision to perform an imaging examination should ultrasonography may be more appropriate than transvagi- be based on the clinical judgment of the health care pro- nal ultrasonography for evaluation. vider with consideration of the cost and benefit to the patient (32). Measurement of endometrial thickness in Age-Based Common Differential premenopausal women is not helpful in the evaluation Diagnosis ^ of AUB. 13–18 Years How do transvaginal ultrasonography, In adolescents, AUB most frequently occurs as a result sonohysterography, and magnetic resonance of persistent anovulation due to the immaturity or dys- imaging compare in the assessment of regulation of the hypothalamic–pituitary–ovarian axis uterine abnormalities? and represents normal physiology (27). Abnormal uterine bleeding in adolescents also may be due to hormonal Transvaginal ultrasonography is useful as a screening contraceptive use, pregnancy, pelvic infection, coagulopa- test to assess the endometrial cavity for leiomyomas and thies, or tumors (28). As many as 19% of adolescents with polyps. Although transvaginal ultrasonography is help- AUB who require hospitalization may have an underlying ful for evaluating the myometrium itself, its sensitivity coagulopathy (29, 30), which emphasizes the importance and specificity for evaluating intracavitary pathology are of screening for coagulation disorders in these patients. only 56% and 73%, respectively (33). Substantial evidence exists to indicate that sonohys- 19–39 Years terography is superior to transvaginal ultrasonography Abnormal uterine bleeding most frequently occurs in in the detection of intracavitary lesions, such as polyps women aged 19–39 years as a result of pregnancy, struc- and submucosal leiomyomas (33–41). Only sonohys- tural lesions (eg, leiomyomas or polyps), anovulatory terography can distinguish between focal versus uniform cycles (eg, PCOS), use of hormonal contraception, and thickening of the endometrium and structural abnormali- endometrial hyperplasia. Endometrial cancer is less com- ties. A localized thickening of the endometrium may not mon but may occur in this age group (31). yield adequate sampling with an endometrial biopsy. 4 Practice Bulletin No. 128  Uterine evaluation Enhanced risk of hyperplasia Enhanced risk of a or neoplasia or both structural abnormality Yes No Yes Office endometrial biopsy TVUS Adequate Yes Normal cavity? No specimen? No Yes or Hysteroscopy SIS +/- biopsy Atypical AUB-E or O hyperplasia/ No (presumptive) Target lesion? CA? No Can’t assess Yes Yes Consider MRI Management of AUB-M AUB-LSM, AUB-P, AUB-A Fig. 2. Uterine evaluation. The uterine evaluation is, in part, guided by the medial history and other elements of the clinical situation, such as patient age, presence of an apparent chronic ovulatory disorder, or presence of other risk factors for endometrial hyperplasia or malignancy. For those at increased risk, endometrial biopsy is probably warranted. If there is a risk of structural anomaly, particularly if previous medical therapy has been unsuccessful, evaluation of the uterus should include imaging, at least with a screening transvaginal ultrasonography. Unless the ultrasound image indicates a normal endometrial cavity, it will be necessary to use either or both hys- teroscopy and sonohysterography to determine whether target lesions are present. Such an approach is also desirable if endometrial sampling has not provided an adequate specimen. Uncommonly, these measures are inconclusive or, in the instance of virginal girls and women, not feasible outside of an anesthetized environment. In these instances, magnetic resonance imaging may be of value, if available. Abbreviations: AUB, abnormal uterine bleeding; AUB-P, polyp; AUB-A, adenomyosis; AUB-LSM, leiomyoma submucosal; AUB- M, malignancy and hyperplasia; AUB-O, ovulatory dysfunction; AUB-E, endometrial; CA, carcinoma; MRI, magnetic resonance imag- ing; SIS, sonohysterography; TVUS, transvaginal ultrasonography. Reprinted from Munro MG. Abnormal Uterine Bleeding. Cambridge: Cambridge University Press; 2010. ^p4 ^p7 Compared with transvaginal ultrasonography, sono- submucosal leiomyomas, which may help predict the suc- hysterography also provides better information on the cess of hysteroscopic resection (43, 44). However, there size and location of cavitary abnormalities (38). In a is insufficient evidence to recommend routine three- study that compared the accuracy of several diagnos- dimensional ultrasonography in the evaluation of AUB. tic modalities, sonohysterography was as effective as Routine use of magnetic resonance imaging (MRI) hysteroscopy in detecting structural versus histopatho- in the evaluation of AUB is not recommended. However, logic abnormalities (33). In a large meta-analysis, the MRI may be useful to guide the treatment of myo- presence of intrauterine abnormalities in women with mas, particularly when the uterus is enlarged, contains AUB was 46.6% (42). There are some data that indicate multiple myomas, or precise myoma mapping is of that three-dimensional sonohysterography may be more clinical importance. However, the benefits and costs to accurate than two-dimensional sonohysterography in the patient must be weighed when considering its use. determining the size and depth of myometrial invasion of The superior sensitivity of MRI may be useful when Practice Bul­le­tin No. 128 5 myomectomy is planned, before uterine artery emboli- a previous benign pathology, such as proliferative endo- zation, for the detection of adenomyomas, and before metrium, requires further testing to rule out nonfocal focused ultrasound treatment (45–47). endometrial pathology or a structural pathology, such as a polyp or leiomyoma. Other evaluation methods, such How is ultrasonographic measurement of as transvaginal ultrasonography, sonohysterography, or endometrial thickness useful in the evalua- office hysteroscopy also may be necessary when the tion of abnormal uterine bleeding in various endometrial biopsy is insufficient, nondiagnostic, or can- age groups? not be performed. Hysteroscopy allows direct visualization of endome- Ultrasonographic measurement of endometrial thick- trial cavity abnormalities and the ability to take directed ness is of limited value in detecting benign abnormali- biopsies (26). Hysteroscopy is highly accurate in diag- ties in the premenopausal woman as compared with its nosing endometrial cancer but less useful for detecting ability to exclude malignancy in the postmenopausal hyperplasia (53). Hysteroscopy may be performed in an woman (48–50). There are insufficient data to support office setting or in the operating room, with office hys- the use of endometrial thickness in the evaluation of teroscopy being less expensive, more convenient for the AUB in women of reproductive age who are at low risk. physician and patient, and offering faster recovery and Endometrial thickness varies throughout the menstrual less time off work for the patient (54, 55). Performing cycle in response to hormonal changes, making its diag- hysteroscopy in the operating room has the advantages nostic value in premenopausal women less useful. of general anesthetics and the ability to perform laparos- copy should complications arise. In a meta-analysis that When is endometrial tissue sampling indi- evaluated the accuracy of diagnostic hysteroscopy com- cated in patients with abnormal uterine pared with guided biopsy during hysteroscopy, operative bleeding and how should it be performed? hysteroscopy, or hysterectomy, diagnostic hysteroscopy had an overall success rate of 96.6% (standard deviation, The primary role of endometrial sampling in patients with 5.2%; range, 83–100%), and abnormalities were found AUB is to determine whether carcinoma or premalignant in 46.6% of premenopausal and postmenopausal women lesions are present, although other pathology related to with AUB (42). bleeding may be found. Endometrial tissue sampling should be performed in patients with AUB who are older What tests are useful for diagnosing adeno- than 45 years as a first-line test (see Fig. 2). Endometrial myosis? sampling also should be performed in patients younger than 45 years with a history of unopposed estrogen expo- Adenomyosis can be diagnosed with transvaginal ultra- sure (such as seen in obesity or PCOS), failed medical sonography or MRI and is definitively diagnosed by management, and persistent AUB (3). histopathology. Ultrasonographic findings that support a An office endometrial biopsy is the first-line proce- diagnosis of adenomyosis include heterogeneous myome- dure for tissue sampling in the evaluation of patients with trium, myometrial cysts, asymmetric myometrial thick- AUB. Endometrial sampling may be performed with a ness, and subendometrial echogenic linear striations variety of office aspirators, office or inpatient hysteros- (56–60). Adenomyosis is best visualized with MRI using copy, or by dilation and curettage. A systematic review T2-weighted images (61, 62). The incidence of asymp- showed that endometrial biopsy has high overall accu- tomatic adenomyosis found incidentally on imaging racy in diagnosing endometrial cancer when an adequate studies in women has not been established. In studies that specimen is obtained and when the endometrial process compared the effectiveness of transvaginal ultrasonogra- is global. If the cancer occupies less than 50% of the phy and MRI for the diagnosis of adenomyosis, MRI has surface area of the endometrial cavity, the cancer can be been shown to be somewhere between equal to and supe- missed by a blind endometrial biopsy (51). Further, the rior (61, 63–66). The discrepancies in studies comparing results showed that a positive test result is more accurate the two modalities may be due to different diagnostic for ruling in disease than a negative test result is for rul- criteria for adenomyosis, varying quality of ultrasound ing it out: the posttest probability of endometrial cancer machines over the time spans of the studies, and the was 81.7% (95% confidence interval, 59.7–92.9%) for a experience of the radiologists in diagnosing adenomyo- positive test result and 0.9% (95% confidence interval, sis. Transvaginal ultrasonography may perform less well 0.4–2.4%) for a negative test result (52). Therefore, in the presence of an enlarged uterus or with coexisting these tests are only an endpoint when they reveal cancer myomas (37, 65, 67). These factors and the expense of or atypical complex hyperplasia. Persistent bleeding with MRI have led some experts to recommend transvaginal 6 Practice Bulletin No. 128 ultrasonography as the initial screening test for AUB and The following recommendations and conclusions MRI as a second-line test to be used when the diagnosis are based on limited or inconsistent scientific evi- is inconclusive, when further delineation would affect dence (Level B): patient management, or when coexisting uterine myomas are suspected (59, 60, 62, 65, 67–70). Testing for Chlamydia trachomatis should be con- sidered, especially in patients at high risk of infection. At what point in the evaluation is therapy Hypothyroidism and hyperthyroidism are associated appropriate? with AUB. Screening for thyroid disease with TSH level measurement in women with AUB is reason- In a patient without enhanced risk of endometrial hyper- able and inexpensive. plasia, neoplasia, or structural abnormalities, such as adolescents, a trial of therapy is appropriate. For those at The following recommendations and conclusions increased risk, such as patients with genetic risk factors are based primarily on consensus and expert opin- for endometrial cancer, patients older than 45 years, or patients whose prolonged anovulatory cycles are associ- ion (Level C): ated with unopposed estrogen, initiation of therapy is Endometrial tissue sampling should be performed in appropriate after a complete diagnostic evaluation has patients with AUB who are older than 45 years as a been completed (see Fig. 2). Persistent bleeding despite first-line test (see Fig. 2). therapy requires further evaluation. An appropriate trial The American College of Obstetricians and Gyne- of therapy will depend on the cause of the abnormal cologists supports the adoption of the PALM–COEIN bleeding, the risks and benefits of the therapy, the costs to nomenclature system developed by FIGO to stan- the patient, and the patient’s own desire. Many causes of dardize the terminology used to describe AUB. abnormal bleeding are amenable to medical management with nonsteroidal antiinflammatory drugs, progestins, Some experts recommend transvaginal ultrasonogra- combination oral contraceptives, a levonorgestrel intra- phy as the initial screening test for AUB and MRI as uterine device, or tranexamic acid. For anatomic causes a second-line test to be used when the diagnosis is of abnormal uterine bleeding, such as uterine myomas or inconclusive, when further delineation would affect polyps, surgery may be indicated. Endometrial ablation patient management, or when coexisting uterine myo- and resection are minimally invasive surgical options to mas are suspected. control bleeding in women who have completed child- MRI may be useful to guide the treatment of myo- bearing (71). mas, particularly when the uterus is enlarged, con- tains multiple myomas, or precise myoma mapping is of clinical importance. However, the benefits and Summary of costs to the patient must be weighed when consider- ing its use. Recommendations and Persistent bleeding with a previous benign pathology, Conclusions such as proliferative endometrium, requires further testing to rule out nonfocal endometrial pathology or The following recommendations and conclusions a structural pathology, such as a polyp or leiomyoma. are based on good and consistent scientific evi- dence (Level A): References Substantial evidence exists to indicate that sonohys- terography is superior to transvaginal ultrasonogra- 1. Spencer CP, Whitehead MI. Endometrial assessment re- visited. Br J Obstet Gynaecol 1999;106:623–32. (Level III) phy in the detection of intracavitary lesions, such as [PubMed] ^ polyps and submucosal leiomyomas. 2. Fraser IS, Critchley HO, Munro MG, Broder M. A process In all adolescents with heavy menstrual bleeding and designed to lead to international agreement on terminol- adult patients with a positive screening history for a ogies and definitions used to describe abnormalities of menstrual bleeding. Writing Group for this Menstrual Agree- bleeding disorder, laboratory testing is indicated. ment Process [published erratum appears in Fertil Steril Initial tests should include a CBC with platelets, pro- 2007;88:538]. Fertil Steril 2007;87:466–76. (Level III) thrombin time, and partial thromboplastin time (fibrin- [PubMed] [Full Text] ^ ogen or thrombin time are optional); bleeding time is 3. Munro MG, Critchley HO, Broder MS, Fraser IS. FIGO neither sensitive nor specific and is not indicated. classification system (PALM-COEIN) for causes of abnor- Practice Bul­le­tin No. 128 7  mal uterine bleeding in nongravid women of reproductive Thromb Res 2005;117:81–6; discussion 113–5. (Level III) age. FIGO Working Group on Menstrual Disorders. Int [PubMed] ^ J Gynaecol Obstet 2011;113:3–13. (Level III) [PubMed] 18. Valente MJ, Abramson N. Easy bruisability. South Med J [Full Text] ^ 2006;99:366–70. (Level III) [PubMed] ^ 4. Livingstone M, Fraser IS. Mechanisms of abnormal uterine 19. Kirtava A, Drews C, Lally C, Dilley A, Evatt B. Medical, bleeding. Hum Reprod Update 2002;8:60–7. (Level III) reproductive and psychosocial experiences of women [PubMed] [Full Text] ^ diagnosed with von Willebrand’s disease receiving care 5. Smith SK, Abel MH, Kelly RW, Baird DT. A role for in haemophilia treatment centres: a case-control study. prostacyclin (PGi2) in excessive menstrual bleeding. Haemophilia 2003;9:292–7. (Level II-3) [PubMed] ^ Lancet 1981;1:522–4. (Level II-3) [PubMed] ^ 20. Kouides PA. Current understanding of von Willebrand’s 6. Adelantado JM, Rees MC, Lopez Bernal A, Turnbull AC. disease in women—some answers, more questions. Increased uterine prostaglandin E receptors in menor- Haemophilia 2006;12(suppl 3):143–51. (Level III) rhagic women. Br J Obstet Gynaecol 1988;95:162–5. [PubMed] ^ (Level III) [PubMed] ^ 21. Philipp CS, Faiz A, Dowling NF, Beckman M, Owens S, 7. Smith SK, Abel MH, Kelly RW, Baird DT. Prostaglandin Ayers C, et al. Development of a screening tool for identi- synthesis in the endometrium of women with ovular dys- fying women with menorrhagia for hemostatic evaluation. functional uterine bleeding. Br J Obstet Gynaecol 1981; Am J Obstet Gynecol 2008;198:163.e1,163.e8. (Level II-3) 88:434–42. (Level III) [PubMed] ^ [PubMed] ^ 8. Dockeray CJ, Sheppard BL, Daly L, Bonnar J. The 22. Jennings I, Kitchen S, Woods TA, Preston FE. Laboratory fibrinolytic enzyme system in normal menstruation and performance of haemophilia centres in developing coun- excessive uterine bleeding and the effect of tranexamic tries: 3 years’ experience of the World Federation of acid. Eur J Obstet Gynecol Reprod Biol 1987;24:309–18. Hemophilia External Quality Assessment Scheme. Haemo- (Level II-3) [PubMed] ^ philia 1998;4:739–46. (Level II-3) [PubMed] ^ 9. Gleeson N, Devitt M, Sheppard BL, Bonnar J. Endometrial 23. Foster PA. The reproductive health of women with von fibrinolytic enzymes in women with normal menstruation Willebrand Disease unresponsive to DDAVP: results of and dysfunctional uterine bleeding. Br J Obstet Gynaecol an international survey. On behalf of the Subcommittee on 1993;100:768–71. (Level II-3) [PubMed] ^ von Willebrand Factor of the Scientific and Standardiza- 10. James AH. More than menorrhagia: a review of the obstet- tion Committee of the ISTH. Thromb Haemost 1995;74: ric and gynaecological manifestations of bleeding dis- 784–90. (Level II-3) [PubMed] ^ orders. Haemophilia 2005;11:295–307. (Level III) 24. Krassas GE. Thyroid disease and female reproduction. [PubMed] ^ Fertil Steril 2000;74:1063–70. (Level III) [PubMed] [Full 11. Shankar M, Lee CA, Sabin CA, Economides DL, Kadir Text] ^ RA. von Willebrand disease in women with menorrhagia: 25. Attia AH, Youssef D, Hassan N, El-Meligui M, Kamal M, a systematic review. BJOG 2004;111:734–40. (Level III) Al-Inany H. Subclinical hyperthyroidism as a poten- [PubMed] [Full Text] ^ tial factor for dysfunctional uterine bleeding. Gynecol 12. Dilley A, Drews C, Miller C, Lally C, Austin H, Endocrinol 2007;23:65–8. (Level II-3) [PubMed] [Full Ramaswamy D, et al. von Willebrand disease and other Text] ^ inherited bleeding disorders in women with diagnosed 26. Hysteroscopy. Technology Assessment No. 7. American menorrhagia. Obstet Gynecol 2001;97:630–6. (Level II-3) College of Obstetricians and Gynecologists. Obstet Gyne- [PubMed] [Obstetrics & Gynecology] ^ col 2011;117:1486–91. (Level III) [PubMed] [Obstetrics 13. Kadir RA, Economides DL, Sabin CA, Owens D, Lee CA. & Gynecology] ^ Frequency of inherited bleeding disorders in women 27. Menstruation in girls and adolescents: using the menstrual with menorrhagia. Lancet 1998;351:485–9. (Level II-3) cycle as a vital sign. ACOG Committee Opinion No. 349. [PubMed] [Full Text] ^ American College of Obstetricians and Gynecologists. 14. National Heart, Lung, and Blood Institute. The diagnosis, Obstet Gynecol 2006;108:1323–8. (Level III) [PubMed] evaluation, and management of von Willebrand Disease. [Obstetrics & Gynecology] ^ NIH Publication No. 08-5832. Bethesda (MD): NHLBI; 28. Slap GB. Menstrual disorders in adolescence. Best Pract 2007. Available at: http://www.nhlbi.nih.gov/guidelines/ Res Clin Obstet Gynaecol 2003;17:75–92. (Level III) vwd/vwd.pdf. Retrieved February 15, 2012. (Level III) ^ [PubMed] [Full Text] ^ 15. James AH, Manco–Johnson MJ, Yawn BP, Dietrich 29. Claessens EA, Cowell CA. Acute adolescent menorrha- JE, Nichols WL. Von Willebrand disease: key points gia. Am J Obstet Gynecol 1981;139:277–80. (Level III) from the 2008 National Heart, Lung, and Blood Institute [PubMed] ^ guidelines. Obstet Gynecol 2009;114:674–8. (Level III) 30. Minjarez DA, Bradshaw KD. Abnormal uterine bleed- [PubMed] [Obstetrics & Gynecology] ^ ing in adolescents. Obstet Gynecol Clin North Am 2000; 16. Basila D, Yuan CS. Effects of dietary supplements on 27:63–78. (Level III) [PubMed] ^ coagulation and platelet function. Thromb Res 2005; 31. Managment of endometrial cancer. ACOG Practice 117:49–53; discussion 65–7. (Level II-3) [PubMed] ^ Bulletin No. 65. American College of Obstetricians 17. Wittkowsky AK. A systematic review and inventory of and Gynecologists. Obstet Gynecol 2005;106:413–25. supplement effects on warfarin and other anticoagulants. (Level III) [PubMed] [Obstetrics & Gynecology] ^ 8 Practice Bulletin No. 128 32. The role of transvaginal ultrasonography in the evaluation 43. Salim R, Lee C, Davies A, Jolaoso B, Ofuasia E, Jurkovic D. of postmenopausal bleeding. ACOG Committee Opinion A comparative study of three-dimensional saline infusion No. 440. American College of Obstetricians and Gyne- sonohysterography and diagnostic hysteroscopy for the cologists. Obstet Gynecol 2009;114:409–11. (Level III) classification of submucous fibroids. Hum Reprod 2005; [Obstetrics & Gynecology] ^ 20:253–7. (Level III) [PubMed] ^ 33. Kelekci S, Kaya E, Alan M, Alan Y, Bilge U, 44. de Kroon CD, Louwe LA, Trimbos JB, Jansen FW. The Mollamahmutoglu L. Comparison of transvaginal sonog- clinical value of 3-dimensional saline infusion sonography raphy, saline infusion sonography, and office hysterosco- in addition to 2-dimensional saline infusion sonography in py in reproductive-aged women with or without abnormal women with abnormal uterine bleeding: work in progress. J uterine bleeding. Fertil Steril 2005;84:682–6. (Level II-3) Ultrasound Med 2004;23:1433–40. (Level II-3) [PubMed] [PubMed] [Full Text] ^ [Full Text] ^ 34. Alborzi S, Parsanezhad ME, Mahmoodian N, Alborzi S, 45. Levens ED, Wesley R, Premkumar A, Blocker W, Alborzi M. Sonohysterography versus transvaginal sonog- Nieman LK. Magnetic resonance imaging and trans- raphy for screening of patients with abnormal uterine vaginal ultrasound for determining fibroid burden: implica- bleeding. Int J Gynaecol Obstet 2007;96:20–3. (Level II-3) tions for research and clinical care. Am J Obstet Gynecol [PubMed] [Full Text] ^ 2009;200:537.e1–537.e7. (Level II-3) [PubMed] [Full Text] 35. Guven MA, Bese T, Demirkiran F. Comparison of hydro- ^ sonography and transvaginal ultrasonography in the 46. Dueholm M, Lundorf E, Hansen ES, Ledertoug S, Olesen F. detection of intracavitary pathologies in women with Accuracy of magnetic resonance imaging and transvagi- abnormal uterine bleeding. Int J Gynecol Cancer 2004; nal ultrasonography in the diagnosis, mapping, and mea- 14:57–63. (Level II-3) [PubMed] ^ surement of uterine myomas. Am J Obstet Gynecol 2002; 36. de Vries LD, Dijkhuizen FP, Mol BW, Brolmann HA, 186:409 –15. (Level II-3) [PubMed] ^ Moret E, Heintz AP. Comparison of transvaginal sonog- 47. Zawin M, McCarthy S, Scoutt LM, Comite F. High-field raphy, saline infusion sonography, and hysteroscopy in MRI and US evaluation of the pelvis in women with leio- premenopausal women with abnormal uterine bleeding. J myomas. Magn Reson Imaging 1990;8:371–6. (Level III) Clin Ultrasound 2000;28:217–23. (Level II-3) [PubMed] [PubMed] ^ ^ 48. Dueholm M, Jensen ML, Laursen H, Kracht P. Can 37. Dueholm M, Forman A, Jensen ML, Laursen H, Kracht P. the endometrial thickness as measured by trans-vaginal Transvaginal sonography combined with saline contrast sonohysterography in evaluating the uterine cavity in sonography be used to exclude polyps or hyperplasia in premenopausal patients with abnormal uterine bleeding. pre-menopausal patients with abnormal uterine bleeding? Ultrasound Obstet Gynecol 2001;18:54 – 61. (Level II-3) Acta Obstet Gynecol Scand 2001;80:645–51. (Level II-3) [PubMed] [Full Text] ^ [PubMed] [Full Text] ^ 38. Schwarzler P, Concin H, Bosch H, Berlinger A, 49. Breitkopf DM, Frederickson RA, Snyder RR. Detection Wohlgenannt K, Collins WP, et al. An evaluation of sono- of benign endometrial masses by endometrial stripe mea- hysterography and diagnostic hysteroscopy for the assess- surement in premenopausal women. Obstet Gynecol 2004; ment of intrauterine pathology. Ultrasound Obstet Gynecol 104:120 –5. (Level II-3) [PubMed] [Obstetrics & 1998;11:337– 42. (Level II-3) [PubMed] [Full Text] ^ Gynecology] ^ 39. Farquhar C, Ekeroma A, Furness S, Arroll B. A systematic 50. Dijkhuizen FP, De Vries LD, Mol BW, Brolmann HA, review of transvaginal ultrasonography, sonohysterogra- Peters HM, Moret E, et al. Comparison of transvaginal phy and hysteroscopy for the investigation of abnormal ultrasonography and saline infusion sonography for the uterine bleeding in premenopausal women. Acta Obstet detection of intracavitary abnormalities in premeno- Gynecol Scand 2003;82:493 –504. (Level III) [PubMed] pausal women. Ultrasound Obstet Gynecol 2000;15:372–6. [Full Text] ^ (Level II-3) [PubMed] [Full Text] ^ 40. Botsis D, Papagianni V, Makrakis E, Aravantinos L, 51. Guido RS, Kanbour-Shakir A, Rulin MC, Christopherson Creatsas G. Sonohysterography is superior to transvagi- WA. Pipelle endometrial sampling. Sensitivity in the nal sonography for the diagnostic approach of irregular detection of endometrial cancer. J Reprod Med 1995;40: uterine bleeding in women of reproductive age. J Clin 553 –5. (Level II-3) [PubMed] ^ Ultrasound 2006;34:434 –9. (Level II-3) [PubMed] ^ 52. Clark TJ, Mann CH, Shah N, Khan KS, Song F, Gupta JK. 41. Ryu JA, Kim B, Lee J, Kim S, Lee SH. Comparison of Accuracy of outpatient endometrial biopsy in the diagnosis transvaginal ultrasonography with hysterosonography of endometrial cancer: a systematic quantitative review. as a screening method in patients with abnormal uterine BJOG 2002;109:313–21. (Meta-analysis) [PubMed] [Full bleeding. Korean J Radiol 2004;5:39–46. (Level II-3) Text] ^ [PubMed] [Full Text] ^ 53. Clark TJ, Voit D, Gupta JK, Hyde C, Song F, Khan KS. 42. van Dongen H, de Kroon CD, Jacobi CE, Trimbos JB, Accuracy of hysteroscopy in the diagnosis of endometrial Jansen FW. Diagnostic hysteroscopy in abnormal uterine cancer and hyperplasia: a systematic quantitative review. bleeding: a systematic review and meta-analysis. BJOG JAMA 2002;288:1610–21. (Meta-analysis) [PubMed] ^ 2007;114:664–75. (Meta-analysis) [PubMed] [Full Text] 54. Marsh F, Kremer C, Duffy S. Delivering an effective out- ^ patient service in gynaecology. A randomised controlled Practice Bul­le­tin No. 128 9  trial analysing the cost of outpatient versus daycase hys- 63. Dueholm M, Lundorf E, Hansen ES, Sorensen JS, teroscopy. BJOG 2004;111:243–8. (Cost-benefit analysis) Ledertoug S, Olesen F. Magnetic resonance imaging and [PubMed] [Full Text] ^ transvaginal ultrasonography for the diagnosis of adenomy- 55. Hidlebaugh D. A comparison of clinical outcomes and osis. Fertil Steril 2001;76:588–94. (Level II-3) [PubMed] cost of office versus hospital hysteroscopy. J Am Assoc [Full Text] ^ Gynecol Laparosc 1996;4:39–45. (Level II-3) [PubMed] 64. Levgur M. Diagnosis of adenomyosis: a review. J Reprod ^ Med 2007;52:177–93. (Level III) [PubMed] ^ 56. Kepkep K, Tuncay YA, Goynumer G, Tutal E. Trans- 65. Bazot M, Cortez A, Darai E, Rouger J, Chopier J, Antoine vaginal sonography in the diagnosis of adenomyosis: which JM, et al. Ultrasonography compared with magnetic reso- findings are most accurate? Ultrasound Obstet Gynecol nance imaging for the diagnosis of adenomyosis: correla- 2007;30:341–5. (Level II-3) [PubMed] [Full Text] ^ tion with histopathology. Hum Reprod 2001;16:2427–33. (Level II-3) [PubMed] ^ 57. Atri M, Reinhold C, Mehio AR, Chapman WB, Bret PM. Adenomyosis: US features with histologic correlation in 66. Ascher SM, Arnold LL, Patt RH, Schruefer JJ, Bagley an in-vitro study. Radiology 2000;215:783–90. (Level III) AS, Semelka RC, et al. Adenomyosis: prospective com- [PubMed] [Full Text] ^ parison of MR imaging and transvaginal sonography. Radiology 1994;190:803–6. (Level III) [PubMed] ^ 58. Bromley B, Shipp TD, Benacerraf B. Adenomyosis: sono- graphic findings and diagnostic accuracy. J Ultrasound 67. Bazot M, Darai E, Rouger J, Detchev R, Cortez A, Uzan S. Med 2000;19:529–34; quiz 535–6. (Level III) [PubMed] Limitations of transvaginal sonography for the diagnosis [Full Text] ^ of adenomyosis, with histopathological correlation. Ultra- sound Obstet Gynecol 2002;20:605–11. (Level II-3) 59. Reinhold C, Atri M, Mehio A, Zakarian R, Aldis AE, [PubMed] [Full Text] ^ Bret PM. Diffuse uterine adenomyosis: morphologic cri- 68. Moghadam R, Lathi RB, Shahmohamady B, Saberi NS, teria and diagnostic accuracy of endovaginal sonography. Nezhat CH, Nezhat F, et al. Predictive value of magnetic Radiology 1995;197:609–14. (Level II-3) [PubMed] ^ resonance imaging in differentiating between leiomyoma 60. Reinhold C, Tafazoli F, Mehio A, Wang L, Atri M, and adenomyosis. JSLS 2006;10:216–9. (Level II-3) Siegelman ES, et al. Uterine adenomyosis: endovaginal US [PubMed] [Full Text] ^ and MR imaging features with histopathologic correlation. 69. Dueholm M. Transvaginal ultrasound for diagnosis of Radiographics 1999;19:S147–60. (Level III) [PubMed] ^ adenomyosis: a review. Best Pract Res Clin Obstet 61. Reinhold C, McCarthy S, Bret PM, Mehio A, Atri M, Gynaecol 2006;20:569–82. (Level III) [PubMed] [Full Zakarian R, et al. Diffuse adenomyosis: comparison of Text] ^ endovaginal US and MR imaging with histopathologic cor- 70. Arnold LL, Ascher SM, Schruefer JJ, Simon JA. The non- relation. Radiology 1996;199:151–8. (Level II-3) [PubMed] surgical diagnosis of adenomyosis. Obstet Gynecol 1995;86: ^ 461–5. (Level III) [PubMed] [Obstetrics & Gynecology] ^ 62. Dueholm M, Lundorf E. Transvaginal ultrasound or MRI 71. Endometrial ablation. ACOG Practice Bulletin No. 81. for diagnosis of adenomyosis. Curr Opin Obstet Gynecol American College of Obstetricians and Gynecologists. 2007;19:505–12. (Level III) [PubMed] ^ Obstet Gynecol 2007;109:1233–48. (Level III) [PubMed] [Obstetrics & Gynecology] ^ 10 Practice Bulletin No. 128  Copyright July 2012 by the American College of Ob­ste­t- The MEDLINE database, the Cochrane Library, and the ri­cians and Gynecologists. All rights reserved. No part of this American College of Obstetricians and Gynecologists’ publication may be reproduced, stored in a re­triev­al sys­tem, own internal resources and documents were used to con­ posted on the Internet, or transmitted, in any form or by any duct a lit­er­a­ture search to lo­cate rel­e­vant ar­ti­cles pub­lished means, elec­tron­ic, me­chan­i­cal, photocopying, recording, or be­tween January 1990 and November 2008. The search oth­er­wise, without prior written permission from the publisher. was re­strict­ed to ar­ti­cles pub­lished in the English lan­guage. Pri­or­i­ty was given to articles re­port­ing results of orig­i­nal Requests for authorization to make photocopies should be re­search, although re­view ar­ti­cles and com­men­tar­ies also directed to Copyright Clearance Center, 222 Rosewood Drive, were consulted. Ab­stracts of re­search pre­sent­ed at sym­po­ Danvers, MA 01923, (978) 750-8400. sia and sci­en­tif­ic con­fer­enc­es were not con­sid­ered adequate ISSN 1099-3630 for in­clu­sion in this doc­u­ment. Guide­lines pub­lished by The American College of Obstetricians and Gynecologists or­ga­ni­za­tions or in­sti­tu­tions such as the Na­tion­al In­sti­tutes 409 12th Street, SW, PO Box 96920, Washington, DC 20090-6920 of Health and the Amer­i­can Col­lege of Ob­ste­tri­cians and Gy­ne­col­o­gists were re­viewed, and ad­di­tion­al studies were Diagnosis of abnormal uterine bleeding in reproductive-aged women. located by re­view­ing bib­liographies of identified articles. Practice Bulletin No. 128. American College of Obstetricians and Gyne- When re­li­able research was not available, expert opinions cologists. Obstet Gynecol 2012;120:197–206. from ob­ste­tri­cian–gynecologists were used. Studies were reviewed and evaluated for qual­i­ty ac­cord­ing to the method outlined by the U.S. Pre­ven­tive Services Task Force: I Evidence obtained from at least one prop­ er­ ly de­signed randomized controlled trial. II-1 Evidence obtained from well-designed con­ trolled tri­als without randomization. II-2 Evidence obtained from well-designed co­ hort or case–control analytic studies, pref­er­a­bly from more than one center or research group. II-3 Evidence obtained from multiple time series with or with­out the intervention. Dra­mat­ic re­sults in un­con­ trolled ex­per­i­ments also could be regarded as this type of ev­i­dence. III Opinions of respected authorities, based on clin­i­cal ex­pe­ri­ence, descriptive stud­ies, or re­ports of ex­pert committees. Based on the highest level of evidence found in the data, recommendations are provided and grad­ed ac­cord­ing to the following categories: Level A—Recommendations are based on good and con­ sis­tent sci­en­tif­ic evidence. Level B—Recommendations are based on limited or in­con­ sis­tent scientific evidence. Level C—Recommendations are based primarily on con­ sen­sus and expert opinion. Practice Bul­le­tin No. 128 11