Due to inconsistent use of nomenclature for abnormal uterine bleeding (AUB) among clinicians, researchers, and patients, in 2011 the International Federation of Gynecology and Obstetrics proposed terminology using plain language that also serves as a classification system for etiologies of AUB.1 This was endorsed by the American Congress of Obstetricians and Gynecologists (ACOG).2 The term AUB can be further classified as AUB/heavy menstrual bleeding (HMB) (replacing the term “menorrhagia”) or AUB/intermenstrual bleeding (IMB; replacing the term “metrorrhagia”). The working group recommended abandoning the term “dysfunctional uterine bleeding.”
Each of the above descriptive terms is further qualified by an abbreviation that describes the cause of AUB and is divided into structural (PALM [Polyp, Adenomyosis, Leiomyoma, and Malignancy and hyperplasia]) or nonstructural (COEIN [Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, and Not yet classified]). Thus, AUB secondary to a uterine polyp is described as AUB-P. Because nonstructural causes are the most common causes of AUB in adolescents, the remainder of this article focuses on this area. An example of AUB-C is HMB secondary to von Willebrand’s disease (vWD). By convention, AUB-C also includes iatrogenic causes such as anticoagulant drug use. AUB-O encompasses much of AUB seen in adolescents, including perimenarchal ovulatory dysfunction secondary to an immature hypothalamic-pituitary-ovarian axis and endocrinopathies (eg, polycystic ovary syndrome [PCOS]). An example of AUB/IMB-E is AUB caused by endometrial inflammation secondary to sexually transmitted infections (STIs). Bleeding occurring after insertion of the contraceptive implant or intrauterine system (IUS) or associated with imperfect compliance with combination hormonal contraceptives is termed AUB-I. AUB-N includes bleeding related to an arteriovenous malformation.
History and Physical
HMB is defined as >80 mL blood loss per period or periods lasting longer than 7 days.3 Clinical features most strongly associated with HMB include: (1) need to change sanitary protection every 1 to 2 hours, (2) poor iron status, (3) passage of clots greater than a quarter in diameter, (4) large number of products used during the period, and (5) need to change protection overnight.4 Adolescents are at risk of irregular bleeding and HMB due to immaturity of the hypothalamic-pituitary-ovarian axis and associated anovulatory cycles. On average, regular ovulatory cycles are achieved by 20 months after menarche.5 During anovulatory cycles, estrogen stimulates the endometrium, but without ovulation there is no corpus luteum formation and therefore no progesterone production during the second half of the menstrual cycle. This lack of the stabilizing influence of progesterone on the endometrium can lead to unpredictable bleeding and/or HMB. Hemostatic evaluation should be considered in patients with AUB/HMB. Women and girls with HMB have a 10- to 20-fold increased incidence of vWD as compared to the general population.6 Platelet-function disorders are also more common among individuals with AUB.7 Conversely, 76% of women with known bleeding disorders have HMB.8
Important elements of the history include assessing onset of menarche, cycle length, duration of periods, number and type (eg, regular, super) of sanitary products used, need to change products at night, whether concurrent use of pads and tampons is needed to achieve adequate sanitary protection, missed days of school, and bleeding onto clothes. A complete sexual history and general medical history is helpful. Patients should be asked about recent weight changes, symptoms of thyroid dysfunction, and symptoms of anemia (such as dizziness and fatigue). Bleeding symptomology should be assessed, including epistaxis and easy bruising. Postoperative hemorrhage, especially after oropharyngeal procedures, should increase concerns for bleeding disorders.9 A detailed family history assessing for PCOS, menstrual disorders, thyroid disorders, and bleeding symptoms (rather than bleeding disorders) should be obtained. Adolescent endometrial cancer is rare but in case reports, the clinical history typically includes severe obesity and 2 to 3 years of AUB that is unresponsive to medical therapy.10
A thorough physical examination should include orthostatic blood pressure and pulse measurements to aid in assessment of hemostatic stability. Clinicians should observe for pallor, tachycardia, dizziness, and distal perfusion. Examination should include assessment for signs of androgen excess (such as acne, hirsutism), petechiae, ecchymosis, as well as analysis of the thyroid gland and external genital examination for evaluation of possible trauma and identification of the bleeding location. Speculum and bimanual examination should be done in sexually experienced adolescents.
Laboratory evaluation begins with pregnancy testing and complete blood count (CBC) with differential and platelet count to rule out thrombocytopenia.11 In patients with relevant signs and symptoms, testing for thyroid dysfunction and PCOS should be considered. Testing for STIs should be conducted for any sexually experienced adolescent. Ultrasound, ideally using a transvaginal probe, should be considered in the setting of focal abdominal pain, abdominal or pelvic mass, or nonresponse to treatment.
The hematologic laboratory evaluation of AUB is detailed in Table 1. Obtaining a CBC and ferritin allow for evaluation of iron status, with or without associated microcytic anemia. Standard coagulation testing (ie, prothrombin time [PT], activated partial thromboplastin time [aPTT], thrombin time [TT], and fibrinogen) evaluates secondary hemostasis. Depending on the abnormalities of the PT/aPTT, it is possible to isolate a factor deficiency. Prolongation of the PT alone is associated with factor VII deficiency, whereas prolongation of the aPTT alone is associated with deficiencies of factors VIII, IX, XI, and XII. If both tests are prolonged, consider common pathway deficiencies (ie, factors II, V, X, and fibrinogen) or combined-factor deficiencies.
Hematologic Evaluation of Abnormal Uterine Bleeding
The von Willebrand profile typically consists of a von Willebrand factor (vWF) antigen (total vWF protein), vWF activity (activity based on ristocetin-induced platelet aggregation), a factor VIII level, and vWF multimer analysis. VWD is the most common bleeding disorder, with an incidence up to 1% of the population.12,13 The most common type of vWD is type 1, a quantitative deficiency of vWF, and is associated with low vWF antigen and activity with a normal multimer analysis. Type 2 vWD is associated with qualitative defects of the vWF protein. Type 2 vWD may exhibit an abnormal multimer analysis or discrepancies between the antigen and activity. Type 3 vWD is associated with a complete deficit of the vWF protein.14 For a patient with a significant bleeding history and nondiagnostic initial testing, a platelet-function disorder should be considered. The most widely available assays are the standard bleeding time and the Platelet Function Analyser-100 (PFA-100; Siemans Healthcare, Malvern, PA), which assays whole blood platelet aggregation under flow conditions in response to collagen/epinephrine and collagen/ADP.15 However, data suggest that neither the bleeding time nor the PFA-100 is sensitive for diagnosis of platelet aggregation defects.15,16 Thus, we would suggest initiating evaluation for platelet-function disorders using platelet aggregometry17 in consultation with a hematologist.
Combined-hormonal contraception is generally the first-line treatment for AUB.11 The hormonal content of combined oral contraceptive pills (COCPs) leads to increases in fibrinogen, prothrombin, Factors VII and VIII, and vWF, leading to decreased bleeding.18 The contraceptive patch and ring are expected to have similar effects. Extended cycle COCPs can be used. For women with AUB who have contraindications to exogenous estrogen, progestin-only methods, such as progestin-only pills,19 cyclic progestins, or high-dose daily oral progestins,20 are used.11 Depo-medroxyprogesterone acetate injections also lead to overall reduction in blood loss and improvement in anemia, with 50% of women achieving amenorrhea after 1 year of use.21 Subdermal implantable contraception leads to overall reduction in blood loss and improvement in anemia;22 however, women should be counseled about the lack of predictability of bleeding associated with this method.
In 2007, ACOG recommended that IUSs be considered among first-line contraceptives even for nulliparous young women, and this has been extended to all long-acting reversible contraceptives.23 In 2014, the American Academy of Pediatrics issued similar recommendations.24 The Centers for Disease Control and Prevention support use of both the copper and 52-mg levonorgestrel-releasing IUS among nulliparous women, including in those younger than age 20 years.25 The 52-mg levonorgestrel IUS, which is approved by the US Food and Drug Administration (FDA) for treatment of HMB,26 is associated with decreased menstrual blood loss of 86% by 3 months of use and 97% by 1 year.27 The 52-mg levonorgestrel IUS is more effective in treating HMB than other FDA-approved and off-label medical therapies, including nonsteroidal anti-inflammatory drugs, COCPs, and daily progestin.28 In 2008, an expert panel stated that the second choice of therapy for HMB associated with vWD, after COCPs, is the 52-mg levonorgestrel IUS.18,29 Because more data on the effectiveness of the 52-mg levonorgesterel IUS has become available since 2008, more recent statements released by the ACOG have not given preference to particular management strategies for HMB in women with inherited bleeding disorders.30,31
The efficacy of antifibrinolytics, especially tranexamic acid (TXA), for treatment of AUB is well documented.27,32–34 TXA improves AUB in patients with and without bleeding disorders.32,33 Desmopressin acetate, a synthetic analog of vasopression, stimulates release of vWF and factor VIII from endothelium and is commonly used to treat both type 1 vWD and mild hemophilia A.35 Desmopressin is an effective treatment for people with vWD and AUB,33 but no studies have been conducted among patients without bleeding disorders. There are no published data regarding the safety and/or efficacy of the combined use of COCPs and desmopressin or TXA.
An international expert panel provided guidance on the management of acute HMB in women with and without underlying bleeding disorders.36 Some therapies are more appropriate for adolescents for whom fertility preservation is desired. Referral to a gynecologist experienced with adolescent acute HMB should be made when initial medical therapy fails. Transfer of the patient to a tertiary care center may be necessary. Endometrial balloon tamponade via a large French urinary catheter with 30-mL balloon has been used as an adjunct therapy while awaiting onset of additional hemostatic or hormonal therapies.37 Dilation and curettage (D&C) is rarely indicated in adolescents unless tissue diagnosis is needed. Endometrial tissue sampling is recommended in adolescents with a clinical history for possible malignancy when a thorough investigation of potential other causes fails to demonstrate an etiology or in patients with suspicion of a hereditary cancer syndrome.38,39 D&C was not effective in controlling HMB and actually resulted in greater blood loss when attempted in women with VWD.36 Uterine artery embolization should only be used as a life-saving measure in young women.40 The embolic agent that provides the best chance of recanalization and improved future fertility has not yet been established as a therapy in adolescents due to the rarity of its use. Endometrial ablation as an alternative to hysterectomy has been successfully used in women who are poor surgical candidates, but postprocedure pregnancy is not recommended due to both fetal and maternal complications.41 Although hysterectomy is the most successful surgical treatment for eliminating HMB, it should be delayed in adolescents in favor of all medical therapies for HMB, including recombinant factor VIIa and the above-mentioned less invasive and permanent procedures.
- Munro MG, Critchley HO, Broder MS, Fraser ISFIGO Working Group on Menstrual Disorders. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011;113(1):3–13. doi:10.1016/j.ijgo.2010.11.011 [CrossRef]
- Committee on Practice Bulletins—Gynecology. Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012;120(1):197–206. doi:10.1097/AOG.0b013e318262e320 [CrossRef]
- American Academy of Pediatrics Committee on AdolescenceAmerican College of Obstetricians Gynecologists Committee on Adolescent Health Care. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Pediatrics. 2006;118(5):2245–2250. doi:10.1542/peds.2006-2481 [CrossRef]
- Warner PE, Critchley HO, Lumsden MA, Campbell-Brown M, Douglas A, Murray GD. 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(5):1216–1223. doi:10.1016/j.ajog.2003.11.015 [CrossRef]
- Mitan LAP, Slap GB. Dysfunctional uterine bleeding. In: Neinstein LS, Gordon CM, Katzman DK, Rosen DS, Woods ER, eds. Adolescent Health Care: A Practical Guide. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2007.
- Shankar M, Lee CA, Sabin CA, Economides DL, Kadir RA. von Willebrand disease in women with menorrhagia: a systematic review. BJOG. 2004;111(7):734–740. doi:10.1111/j.1471-0528.2004.00176.x [CrossRef]
- Vo KT, Grooms L, Klima J, Holland-Hall C, O’Brien SH. Menstrual bleeding patterns and prevalence of bleeding disorders in a multidisciplinary adolescent haematology clinic. Haemophilia. 2013;19(1):71–75. doi:10.1111/hae.12012 [CrossRef]
- Byams VR, Kouides PA, Kulkarni R, et al. Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres. Haemophilia. 2011;17Suppl 1:6–13. doi:10.1111/j.1365-2516.2011.02558.x [CrossRef]
- Sun GH, Auger KA, Aliu O, Patrick SW, DeMonner S, Davis MM. Posttonsillectomy hemorrhage in children with von Willebrand disease or hemophilia. JAMA Otolaryngol Head Neck Surg. 2013;139(3):245–249. doi:10.1001/jamaoto.2013.1821 [CrossRef]
- Liu G, Wang Y, Zhang X, Yuan B, Han C, Xue F. Endometrial carcinoma in a 15-year-old obese patient with persistent uterine bleeding. Gynecol Endocrinol. 2014;30(4):277–279. doi:10.3109/09513590.2013.875156 [CrossRef]
- American College of Obstetricians Gynecologists. ACOG committee opinion no. 557: Management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women. Obstet Gynecol. 2013;121(4):891–896. doi:10.1097/01.AOG.0000428646.67925.9a [CrossRef]
- Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood. 1987;69(2):454–459.
- Werner EJ, Broxson EH, Tucker EL, Giroux DS, Shults J, Abshire TC. Prevalence of von Willebrand disease in children: a multiethnic study. J Pediatr. 1993;123(6):893–898. doi:10.1016/S0022-3476(05)80384-1 [CrossRef]
- Sadler JE, Budde U, Eikenboom JC, et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost. 2006;4(10):2103–2114. doi:10.1111/j.1538-7836.2006.02146.x [CrossRef]
- Hayward CP, Harrison P, Cattaneo M, et al. Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function. J Thromb Haemost. 2006;4(2):312–319. doi:10.1111/j.1538-7836.2006.01771.x [CrossRef]
- Philipp CS, Miller CH, Faiz A, et al. Screening women with menorrhagia for underlying bleeding disorders: the utility of the platelet function analyser and bleeding time. Haemophilia. 2005;11(5):497–503. doi:10.1111/j.1365-2516.2005.01129.x [CrossRef]
- Gresele PSubcommittee on Platelet Physiology. Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH. J Thromb Haemost. 2015;13(2):314–322. doi:10.1111/jth.12792 [CrossRef]
- Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008;14(2):171–232. doi:10.1111/j.1365-2516.2007.01643.x [CrossRef]
- Santos M, Hendry D, Sangi-Haghpeykar H, Dietrich JE. Retrospective review of norethindrone use in adolescents. J Pediatr Adolesc Gynecol. 2014;27(1):41–44. doi:10.1016/j.jpag.2013.09.002 [CrossRef]
- Munro MG, Mainor N, Basu R, Brisinger M, Barreda L. Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: a randomized controlled trial. Obstet Gynecol. 2006;108(4):924–929. doi:10.1097/01.AOG.0000238343.62063.22 [CrossRef]
- Hubacher D, Lopez L, Steiner MJ, Dorflinger L. Menstrual pattern changes from levonorgestrel subdermal implants and DMPA: systematic review and evidence-based comparisons. Contraception. 2009;80(2):113–118. doi:10.1016/j.contraception.2009.02.008 [CrossRef]
- Dilbaz B, Ozdegirmenci O, Caliskan E, Dilbaz S, Haberal A. Effect of etonogestrel implant on serum lipids, liver function tests and hemoglobin levels. Contraception. 2010;81(6):510–514. doi:10.1016/j.contraception.2010.01.014 [CrossRef]
- Committee on Adolescent Health Care Long-Acting Reversible Contraception Working GroupThe Amercian College of Obstetricians Gynecologists. Committee opinion no. 539: adolescents and long-acting reversible contraception: implants and intrauterine devices. Obstet Gynecol. 2012;120(4):983–988. doi:10.1097/AOG.0b013e3182723b7d [CrossRef]
- Ott MA, Sucato GSCommittee on Adolescence. Contraception for adolescents. Pediatrics. 2014;134(4):e1257–1281. doi:10.1542/peds.2014-2300 [CrossRef]
- Centers for Disease Control and Prevention (CDC). US Medical Eligibility Criteria for Contraceptive Use, 2010. MMWR Recomm Rep. 2010;59(RR-4):1–86.
- Bayer Healthcare. Prescribing information for MIRENA (levonorgestrel-releasing intrauterine system); 2014. http://labeling.bayerhealthcare.com/html/products/pi/Mirena_PI.pdf. Accessed August 7, 2015.
- Milsom I, Andersson K, Andersch B, Rybo G. A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagia. Am J Obstet Gynecol. 1991;164(3):879–883. doi:10.1016/S0002-9378(11)90533-X [CrossRef]
- Nelson AL. Levonorgestrel intrauterine system: a first-line medical treatment for heavy menstrual bleeding. Womens Health (Lond Engl). 2010;6(3):347–356. doi:10.2217/whe.10.16 [CrossRef]
- James AH, Kouides PA, Abdul-Kadir R, et al. Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel. Am J Obstet Gynecol. 2009;201(1):12e11–18. doi:10.1016/j.ajog.2009.04.024 [CrossRef]
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Hematologic Evaluation of Abnormal Uterine Bleeding
||Abnormalities to Consider
|Complete blood count
||Anemia, microcytosis, thrombocytopenia
||Low level is indicative of iron deficiency
||Factor VII if prolonged in isolation
|Activated partial thromboplastin time
||Factors VIII, IX, XI, and XII if prolonged in isolation
||If prolonged, hypofibrinogenemia, dysfibrinogenemia, or heparin contamination
||Hypofibrinogenemia or dysfibrinogenemia
|von Willebrand profile
||Should contain von Willebrand Factor antigen, activity, factor VIII level, and multimer analysis
|Platelet aggregation testing
||Assessment for aggregation and secretion abnormalities