Clinical Review & Education JAMA Pediatrics | Review Diagnosis and Management of Heavy Menstrual Bleeding and Bleeding Disorders in Adolescents Claudia Borzutzky, MD; Julie Jaffray, MD Supplemental content IMPORTANCE Heavy menstrual bleeding is a common cause of anemia and reduced quality of life in adolescents. There is a higher prevalence of bleeding disorders in girls with heavy menstrual bleeding than in the general population. Pediatricians should be comfortable with the initial evaluation of heavy menstrual bleeding and the indications for referral to subspecialty care. OBSERVATIONS The most common cause of heavy menstrual bleeding in adolescents is ovulatory dysfunction, followed by coagulopathies. The most common inherited bleeding disorder is von Willebrand disease, and its incidence in adolescents with heavy menstrual bleeding is high. Distinguishing the etiology of heavy menstrual bleeding will guide Author Affiliations: Keck School of treatment, which can include hemostatic medications, hormonal agents, or a combination of Medicine of University of Southern California, Los Angeles (Borzutzky, both. Among hormonal agents, the 52-mg levonogestrel intrauterine device has been shown Jaffray); Division of Adolescent and to be superior in its effect on heavy menstrual bleeding and is safe and effective in Young Adult Medicine, Department adolescents with bleeding disorders. of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, California CONCLUSIONS AND RELEVANCE Anemia, need for transfusion of blood products, and (Borzutzky); Children’s Center for hospitalization may be avoided with prompt recognition, diagnosis, and treatment of heavy Cancer and Blood Diseases, Department of Pediatrics, Children’s menstrual bleeding, especially when in the setting of bleeding disorders. Safe and effective Hospital Los Angeles, Los Angeles, treatment methods are available and can greatly improve quality of life for affected California (Jaffray). adolescents. A multidisciplinary approach to the treatment of girls with bleeding disorders Corresponding Author: Claudia and history of heavy menstrual bleeding is optimal. Borzutzky, MD, Division of Adolescent and Young Adult Medicine, Children’s Hospital JAMA Pediatr. doi:10.1001/jamapediatrics.2019.5040 Los Angeles, 4650 Sunset Blvd, Published online December 30, 2019. M/S 2, Los Angeles, CA 90027 ([email protected]). chieving menarche and having regular menstrual peri- especially when associated with prolonged or frequent menses, can ods are critical developmental milestones in the life of lead to anemia, fatigue, and hemodynamic instability. These may re- A an adolescent girl. However, for many teenagers, men- sult in associated emergency department visits, hospitalizations, the ses can be a source of distress and medical morbidity, particularly need for transfusion of blood products, and the use of oral and intra- when menses is excessively heavy, frequent, or prolonged. This is venoustherapiestostopbloodloss.Bleedingdisordersarenotuncom- especially true when heavy menstrual bleeding (HMB) is associ- moninfemaleadolescents,andprevalenceofBDamonggirlswithHMB ated with a congenital or acquired bleeding disorder (BD). The is much higher than that for the general population.4,5 etiology and management of HMB in adolescents, with and with- out a BD, has been understudied. This review will explore what is known about HMB in adolescents, as well as the coincidence of a Normal Menstrual Cycle and Abnormalities BD with HMB, and how diagnostic work up and management should vary accordingly. in Menstruation: Definitions and Terms Heavy menstrual bleeding is a common problem in adoles- Normal Menstrual Cycle cent girls and a frequent reason for visits to primary care physi- The normal menstrual cycle (Figure 1)6 depends on the feedback cians, as well as referrals to hematology, adolescent medicine loops of estrogen and progesterone on the production of luteiniz- specialists, and gynecologists. Reported prevalence of HMB ing hormone and follicle-stimulating hormone by the pituitary ranges from 34% to 37%.1,2 Quality of life (QOL) can be signifi- gland and on the hypothalamus’s normal function as metronome cantly affected, manifested in missed school days, physical activ- for the hypothalamic-pituitary-ovarian axis.7 According to ACOG, ity limitations, and need for prolonged periods of rest.1 the mean age for menarche in the United States remains around TheAmericanCollegeofObstetriciansandGynecologists(ACOG) 12.5 years; cycle intervals range from 21 to 45 days (averaging 32 has endorsed the use of the menstrual cycle as a vital sign3;ie,anor- days); menstrual flow is 7 days or less; and normal daily menstrual mal menstrual cycle is an essential element of overall health, while an product use ranges from 3 to 6 regular pads or tampons.3 Normal abnormal menstrual cycle can reflect medical illness, iatrogenic prob- cycles may vary up to 9 days in length, although parameters for lems, or hypothalamus-mediated stress. Heavy menstrual bleeding, teenagers have not been well characterized.8 jamapediatrics.com (Reprinted) JAMA Pediatrics Published online December 30, 2019 E1 © 2019 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by Kim Roque on 01/09/2020 Clinical Review & Education Review Diagnosis and Management of Heavy Menstrual Bleeding and Bleeding Disorders in Adolescents Figure 1. Hypothalamic Pituitary Ovarian Axis and Normal Menstrual Cyclea A Hypothalamic pituitary ovarian axis B Normal menstrual cycle Hypothalamus Hypothalamus LH P FSH/LH Endocrine E2 GnRH cycle FSH CRF Pituitary gland T4 TRF Follicular Luteal phase phase T4 Ovarian Dominant follicle histology Corpus luteum Proliferative Secretory phase phase ACTH TSH Cortisone Thyroid Endometrial histology E2 Adrenal inhibin 0 14 28 gland Cycle Day Menses Ovary ACTH indicates adrenocorticotropic hormone; CRF, corticotropin-releasing thyrotropin-releasing factor; T4, thyroxine; TSH, thyrotropin. hormone; E2, estradiol; FSH, follicle-stimulating hormone; GnRH, a Reproduced with permission from Berek, 2012.6 gonadotropin-releasing hormone; LH, luteinizing hormone; TRF, Abnormal Uterine Bleeding Simultaneous to proposing its new classification system, Abnormal uterine bleeding (AUB) is a term recently favored over FIGO issued a recommendation on the nomenclature used to the previously used dysfunctional uterine bleeding (DUB), and per describe menstrual function, in which confusing, previously used ACOG refers to “menstrual flow outside of normal volume, dura- terms such as menorrhagia, metrorrhagia, polymenorrhea, and tion, regularity, or frequency.”9 In 2011, the Federation of Interna- menometrorrhagia are discarded in favor of the terms used in tional Gynecology and Obstetrics (FIGO) proposed a new classifi- Figure 2: HMB and intermenstrual bleeding, as well as heavy and cation system for causes of AUB, PALM-COEIN10 (Polyp, prolonged menstrual bleeding.13 The Federation of International Adenomyosis, Leiomyoma, Malignancy and hyperplasia, Coagu- Gynecology and Obstetrics also suggested parameters for lopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, and Not normal/abnormal menses for the midreproductive years (eTable yet classified) (Figure 2), which was endorsed by ACOG in 20129 in the Supplement); parameters for the perimenarchal years are and revised in 2018.8 not specified. Although HMB, one symptom of AUB, has previously been defined as a quantification of hemoglobin or an estimation of Primary and Secondary Hemostasis menstrual blood loss by volume (>80 mL),11 the newer FIGO A woman’s monthly menstruation takes a large toll on the hemo- recommendations8 endorse the UK National Institute for Health static system. To avoid excessive bleeding, the interaction of pro- and Care Excellence (UK NICE) clinical definition: “excessive men- coagulants and anticoagulants must be balanced. Any quantitative strual blood loss, which interferes with the woman’s physical, or qualitative disruption of the hemostatic system can lead to in- emotional, social and material QOL, and which can occur alone or creased menstrual bleeding. in combination with other symptoms.”12 This definition relies on Primary hemostasis involves the integration of platelets and a the patient’s lived experience, rather than rigid criteria involving glycoprotein called von Willebrand factor (VWF). Initiation of pri- difficult measurements, and should be applied when treating mary hemostasis begins with injury to the blood vessel wall. This adolescents. injury allows exposure of collagen, elastin, and VWF,14 which E2 JAMA Pediatrics Published online December 30, 2019 (Reprinted) jamapediatrics.com © 2019 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by Kim Roque on 01/09/2020 Diagnosis and Management of Heavy Menstrual Bleeding and Bleeding Disorders in Adolescents Review Clinical Review & Education Figure 2. Federation of International Gynecology and Obstetrics Figure 3. Diagnostic Testing for Disorders of Primary Classification for Causes of Abnormal Uterine Bleeding: PALM-COEINa and Secondary Hemostasis PALM: Structural causes of AUB Quantitative platelet Polyp evaluation: Adenomyosis CBC Leiomyoma Qualitative platelet Malignancy and hyperplasia evaluation: VWD evaluation: Collagen evaluation: PFA-100 VWF: Ag, VWF: Rco Abnormal uterine bleeding (AUB) PA PA FVIII activity Heavy menstrual bleeding Hypermobility score Intermenstrual bleeding EM VWF multimers Primary hemostasis