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Patients with excessive bleeding need treatment now. First-line options include progestin-only therapies, the Munro regimen, and DMPA and short-course oral MPA.
Illustration by Alex Baker, DNA Illustrations, Inc.
Dr. Nelson is a professor in the Department of Obstetrics and Gynecology at the David Geffen School of Medicine at the University of California, Los Angeles.
She reports receiving salary/honoraria from Actavis, Bayer, Merk, Pfizer, and Teva; consulting fees from Agile, Bayer, Merk, Pfizer, and Teva; and grants from Bayer, Merk, Pfizer, and Teva.
A 32-year-old G4P2022 with a body mass index (BMI) of 32 kg/m2 presents with a history of heavy and prolonged bleeding for 10 days. She is slightly fatigued but denies any dizziness or shortness of breath. She reports that she has soaked 12 thick sanitary napkins in the last 24 hours. Normally her menses occur every 28 to 32 days and last for 4 days with moderate flow (3–4 pads per day). She relies on her husband’s vasectomy for birth control. She is slightly tachycardic, but has no orthostatic changes in her vital signs. Her hemoglobin is 9.1. Pelvic exam reveals moderate blood flow from her cervical os. She has a slightly enlarged uterus with no signs of infection. Her urine pregnancy test is negative.
Acute abnormal uterine bleeding is not an uncommon challenge facing practitioners who care for women. The new International Federation of Gynecology and Obstetrics (FIGO) classification system defines it as an episode of heavy bleeding that, in the opinion of the clinician, is of sufficient quantity to require immediate intervention to prevent future blood loss.1 The evaluation that a woman with acute abnormal uterine bleeding needs has been outlined in 2 recent American College of Obstetricians and Gynecologists (ACOG) bulletins and one ACOG Committee Opinion.2-4 Those guidelines emphasize that the workup for acute excessive uterine bleeding depends upon a woman’s age, her medical and menstrual history, her risk factors for endometrial pathology, and her prior laboratory results.
This patient is hemodynamically stable and does not need transfusion or hospitalization. It will not be possible to determine her formal diagnosis until the results of her tests are available.1-4 However, the challenge facing the clinician is that the patient needs treatment now to stop her excessive bleeding.
Hormonal management is first-line medical therapy for patients with acute abnormal uterine bleeding.4,5 However, there is no consistency among the hormonal regimens recommended and very little or no scientific evidence of efficacy for any of them. For example, medroxyprogesterone acetate (MPA) 10 mg a day for 10 days is often prescribed in emergency departments. Obstetrician-gynecologists themselves have developed different so-called oral contraceptive (OC) tapers with 4-3-2-1 OC tablets prescribed for consecutive days or 3-3-2-2-1 birth control pills to be taken on specified days.
A recent European Consensus group offered 4 oral options for hormonal treatment of acute bleeding in women without underlying bleeding disorders: birth control pills with either 30 mcg or 50 mcg of ethinyl estradiol (EE) in combination with any progestin to be taken every 6 hours until bleeding stops (with a re-evaluation at 48 hours); norethindrone acetate 5 mg–10 mg every 4 hours; or MPA 10 mg every 4 hours (up to 80 mg per day). Each regimen had an accompanying taper protocol.5 Interestingly, the source for these options was an adolescent health protocol; no clinical studies were cited.
Given the current state of practice, it would be helpful to briefly trace the history of medical management of acute excessive bleeding to appreciate how very weak the evidence is for most of the therapies that are currently recommended, but also to recognize where important evidence is available.4
The earliest reports of medical management of acute bleeding were usually retrospective and involved the use of very high doses of estrogens. For example, for hospitalized adolescents with hemoglobin levels less than 10 g/100 mL, Claessens et al reported using conjugated equine estrogen (CEE)
40 mg intravenously every 4 hours (for up to 12 doses) coupled with 5 mg norethindrone acetate taken orally 4 times a day, to which could be added a combined oral contraceptive (COC) pill containing 5 mg of progestin and 100 to 150 mcg of mestranol given as 2 tablets initially followed by 1 tablet every 6 hours. Antiemetic agents were given if nausea developed. The birth control pill doses were to be gradually tapered over the following month.6
By contrast, the 25-mg doses of CEE given initially, at 3 hours, and at 5 hours by DeVore et al appear modest.7 This is the most frequently cited study on the subject, even though it reported the experiences of only 17 women given estrogen and 17 women given placebo. The mean baseline hemoglobin of these subjects was 12. The outcomes which the authors chose to use for their conclusions were bleeding cessation rates at 5 hours-the time when the double-blinded portion of the study was concluded. At that 5-hour mark, 72% of hormone-treated women had stopped bleeding compared with 38% of those who received normal saline. Of note, at 3 hours, the placebo was more effective (22% CEE vs 36% placebo of women had stopped bleeding). The researchers noted that women with endometritis did not respond to the estrogen therapy.
High-dose COCs became the standard for outpatient treatment of acute excessive bleeding, although there were only 2 prospective studies published in the literature and even though each of those studies reported the experiences of only 9 patients.8,9 These regimens initially called for 50 mcg EE-containing pills to be given 3 to 4 times a day for several days to stop bleeding, and then slowly tapered over a month. Virtually all other reports on this topic were retrospective analyses, review articles, or textbook recommendations.10-14 Over the years, the recommended hormone dose has dramatically diminished. The most recent edition of a highly respected textbook in reproductive endocrinology recommends that any 35 mcg EE-containing birth control pill can be given 2 tablets the first day followed by 1 tablet a day for the remainder of the pill pack.15
Progestin-only therapies were first used to treat adolescent women. Aksu et al reported that all the teen women hospitalized for acute uterine bleeding stopped bleeding within 4 days when given
60 mg to 120 mg MPA on day 1, followed by 20 mg MPA daily for an additional 9 days.16 Bleeding in this patient population is generally due to anovulatory cycling or to bleeding disorders and could, therefore, reasonably have been expected to respond well to such progestin-only therapy.
Munro et al demonstrated that progestin-only therapies could also be successfully used in an outpatient setting to treat adult women with acute excessive uterine bleeding. In the largest prospective, randomized, comparative study of hormonal options, high-dose COCs (n=20) were compared to high-dose MPA (n=20) (Table 1).17
The median age of these women was greater than 40 years and the mean BMIs were 29.0 and 30.3 kg/m2, respectively. Contrary to conventional wisdom, women in the MPA arm responded at least as well as women in the COC arm. All women in the MPA group avoided surgery. In the COC group, 5% (1 woman) needed an emergency surgical procedure.
The percentage of women who stopped bleeding was the same in the MPA and COC groups (75% vs 88%, RR 0.87 [95% CI, 0.56–1.31]). Median time to bleeding cessation was 3 days in both groups. Where the groups did differ, however, was in patient satisfaction; 81% of the MPA patients said they would use the medication again, while only 69% of the COC users said they would do so (RR 1.18 [95% CI, 0.73–0.98]).
Another progestin-only option (3 days of high-dose oral MPA with intramuscular depot medroxyprogesterone acetate [DMPA], Table 2) has been shown to be very effective in rapidly stopping acute abnormal bleeding in a wide range of women judged to be candidates for outpatient therapy. In their single-arm pilot trial, Ammerman et al treated 48 women aged 19–53 years with mean BMI of 34.9 kg/m2 (range 21.5–51.2 kg/m2).18 The mean duration of the presenting episode of bleeding was 30.6 days. The baseline hemoglobin of the subjects was 10.9 g/100 mL. The women reported having used an average of 8.5 sanitary protection pads in the 24 hours prior to presentation.
Women were followed until all bleeding stopped by 5 days. One-quarter of women stopped bleeding in the first 24 hours, and the women who were still bleeding at that time reported far less blood loss; they used only 2 pads in that 24-hour interval. In this study, virtually every woman (44 of the 48) had an endometrial biopsy performed prior to initiation of treatment, following local protocols designed for women who have only episodic access to health care. This liberal use of biopsies provided histology that represented almost the full spectrum of benign lesions seen in practice (Table 3), but all women responded to the same high-dose progestin therapy, including those with endometritis and secretory endometrial tissue. Patient satisfaction was also very high; all the women in this study reported that they would recommend this treatment to a friend. The researchers did not formally follow the subjects beyond the 5-day study period, but they noted that of the few women who did return within 90 days with bleeding complaints, all responded to additional medical therapy.
Practitioners may prefer to offer the short-term (1 month) oral high-dose progestin-only treatment with MPA recommended in the Munro study. That 1-month time frame is usually sufficient to obtain test results and to have the patient consider her longer-term treatment options. For women (or medical systems) with less timely access to follow-up care, the potential of the intermediate-term approach offered in the Ammerman regimen may be more appropriate.
Of course, any bleeding that persists despite one of these therapies warrants further evaluation, often hysteroscopically directed biopsies. It should be noted that no other progestin formulations have been tested for efficacy for this clinical application even though the European Consensus Group has recommended both MPA and norethindrone acetate.
One practical issue that clinicians need to consider is that while ob/gyns may be familiar with these high-dose progestin-only therapies, many pharmacists may not be. Pharmacists are much more accustomed to filling prescriptions for MPA 10 mg and have been known to decline to fill prescriptions for higher doses, assuming they were in error. To help those colleagues recognize that this is not a dosing error, I write “yes, I mean 20 mg” on the prescription itself. Since I have started using this extra notation, no patient has had any problems filling her prescription. When I fail to make this notation, patients have been told that this is a dangerous dose and are not given the medication.
Nonhormonal therapies can also be used in the setting of acute bleeding, but usually as adjuncts to hormonal therapies. Higher-dose nonsteroidal anti-inflammatory agents (NSAIDS) (Table 4) have been shown to reduce blood loss in women with chronic heavy menstrual bleeding by 20%–30% when started at the beginning of menses.19 It is not clear how much NSAIDs contribute to halting acute bleeding when started later, but they may also help control cramping pain. Women with gastritis, bleeding disorders, or platelet function abnormalities should not use NSAIDs.20
The ACOG Committee Opinion also suggests the use of tranexamic acid 1.3 mg by mouth 3 times a day for 5 days, based on a consensus from the previously mentioned international expert panel, although this therapy has not been tested in any clinical trials involving acute bleeding.4,5 The FDA recommends against use of tranexamic acid in women using estrogen-containing pills or in women with a history of venous thromboembolism.21
Once acute bleeding has been stopped, it is important to prevent its recurrence. Longer treatment therapies should be targeted to treat the underlying etiology of a woman’s bleeding and should consider her risk factors for developing future pathology in the context of her near-time fertility desires. Often hormonal therapies are also first-line treatment options for managing chronic heavy or prolonged menses.3,22
For outpatient management of acute abnormal uterine bleeding, hormonal therapies are first-line choices. Progestin-only methods are at least as effective as estrogen-progestin therapies. The Munro regimen with high-dose oral progestin provides a higher level of patient satisfaction than high-dose COCs and can be used safely by greater numbers of women. The DMPA and short-course oral MPA option may be more appropriate for women with challenges accessing medical services.
1. Munro MG, Critchley HO, Fraser IS; FIGO Menstrual Disorders Working Group. The FIGO classification of causes of abnormal uterine bleeding in the reproductive years. Fertil Steril. 2011;95(7):2204–2208.
2. American College of Obstetricians and Gynecologists. Practice Bulletin no. 128: Diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012;120(1):197–206.
3. American College of Obstetricians and Gynecologists. Practice Bulletin no. 136: Management of abnormal uterine bleeding associated with ovulatory dysfunction. Obstet Gynecol. 2013;122(1):176–185.
4. American College of Obstetricians and Gynecologists. Committee Opinion no. 557: Management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women. Obstet Gynecol. 2013;121(4):891–896.
5. James AH, Kouides PA, Abdul-Kadir R, et al. Evaluation and management of acute menorrhagia in women with and without underlying bleeding disorders: consensus from an international expert panel. Eur J Obstet Gynecol Reprod Biol. 2011;158(2):124–134.
6. Claessens EA, Cowell CA. Acute adolescent menorrhagia. Am J Obstet Gynecol. 1981;139(3):277280.
7. 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(3):285–291.
8. Rao KP. Treatment of menstrual disorders with a combination of norgestrel and ethynyl estradiol. Curr Med Pract. 1971;15(1):586–589.
9. Foss GL. A clinical trial of a new totally synthetic low dose progestogen. J Reprod Fertil. 1969;18(1):59–66.
10. Greenblatt RB. Delay of menses test. Pac Med Surg. 1966;74(3):127–130.
11. Gidwani GP. Vaginal bleeding in adolescents. J Reprod Med. 1984;29(6):417–420.
12. Cowan BD, Morrison JC. Management of abnormal genital bleeding in girls and women. N Engl J Med. 1991;324(24):1710–1715.
13. Falcone T, Desjardins C, Bourque J, Granger L, Hemmings R, Quiros E. Dysfunctional uterine bleeding in adolescents. J Reprod Med. 1994;39(10):761–764.
14. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility.7th Edition. Philadelphia, PA. Lippincott Williams & Wilkins. 2004.
15. Fritz MA, Speroff L. Clinical Gynecologic Endocrinology and Infertility. 8th Edition. Philadelphia, PA. Lippincott Williams & Wilkins. 2010.
16. Aksu F, Madazli R, Budak E, Cepni I, Benian A. High-dose medroxyprogesterone acetate for the treatment of dysfunctional uterine bleeding in 24 adolescents. Aust N Z J Obstet Gynaecol. 1997;37(2):228–231.
17. 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.
18. Ammerman SR, Nelson AL. A new progestogen-only medical therapy for outpatient management of acute, abnormal uterine bleeding: a pilot study. Am J Obstet Gynecol. 2013;208(6):499.e1–5.
19. Lethaby A, Augood C, Duckitt K, Farquhar C. Nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding.
Cochrane DatabaseSyst Rev. 200717;(4):CD000400.
20. Kadir RA, McLintock C. Thrombocytopenia and disorders of platelet function in pregnancy. Semin Thromb Hemost. 2011;37(6):640–652.
21. Lysteda [package insert]. Parsippany, NJ: Ferring Pharmaceuticals Inc; 2013.
22. Matteson KA, Rahn DD, Wheeler TL 2nd, et al. Society of Gynecologic Surgeons Systematic Review Group. Nonsurgical management of heavy menstrual bleeding: a systematic review. Obstet Gynecol. 2013;121(3):632–643.