Grand Rounds: New concepts in nongestational acute uterine bleeding

Acute uterine bleeding in a nonpregnant woman can be a life-threatening emergency requiring urgent care in the emergency or operating room. Yet there's no consensus on how to handle this underappreciated challenge. Not to be confused with chronic abnormal uterine bleeding (AUB) per se in nonpregnant women, acute uterine bleeding, as it's called, is heavy enough to require urgent medical intervention. Many of these women, and particularly young women who have just begun to menstruate, have an inherited disorder of systemic hemostasis like von Willebrand disease. Others can have underlying chronic AUB that may or may not be related to discernable structural abnormalities of the genital tract.

After a brief look at the pathogenesis of acute uterine bleeding in nonpregnant reproductive-aged women, we'll provide practical advice on what you need to do first in such an urgent circumstance or emergency and assess medical and surgical management options, with an emphasis on trying outpatient drug regimens before rushing to surgery.

What triggers acute uterine bleeding in reproductive-aged women?

Acute uterine hemorrhage can stem from any one or a combination of factors. For some women, it's instigated by a localized lesion (for example, a submucosal leiomyoma) Other patients can have idiopathic heavy menstrual bleeding (HMB) despite a structurally normal uterus with or without a history of chronic AUB. Even though HMB with no definable structural abnormality often plagues women with a history of cyclic and predictable periods (ovulatory) or irregular and unpredictable uterine bleeding (anovulatory), acute uterine bleeding seems to be more common in anovulatory patients. One thing common to anovulatory women is that their endometriums lack progesterone-dependent biosynthesis of factors important for endometrial hemostasis, namely prostaglandin (PG) F2α and endothelin-1.^1,2

Common culprits. The pathogenesis of anovulatory AUB is systemic and includes immaturity of the hypothalamic-pituitary-ovarian axis (often seen in perimenarchal girls) and several entities either suspected or known to affect the normal functioning of this axis. Irregular, unpredictable bleeding is associated with psychological stress, rapid changes in weight, or excessive exercise-or any combination thereof. Although there's no specific test for what's perhaps the most common culprit-polycystic ovarian syndrome-hyperprolactinemia and hypothyroidism can be diagnosed using appropriate serum measurements.³ We know that in some women, drugs that affect dopamine metabolism also affect ovulatory function.

Fibroids. The causes of AUB associated with uterine leiomyomas continue to puzzle us. We know that most fibroids are asymptomatic, and despite a lack of proof, clinicians would agree that the myomas that cause bleeding are found near or adjacent to the endometrium or otherwise expand the surface area of the endometrium. Accordingly, women with myomas who present with acute uterine bleeding often do so due to idiopathic, usually anovulatory, HMB. Finally, only rarely do arteriovenous malformations contribute to enigmatic AUB, but be sure to include them in your differential diagnosis of women who present with acute HMB.

Hemostasis disorders. Particularly in perimenarchal girls, an inherited systemic disorder of hemostasis accounts for the nongestational acute uterine bleeding. Although once considered rare, we now know that such coagulopathies are fairly common in women with chronic HMB. In fact, 13% of women with "menorrhagia" were found to have biochemical markers of von Willebrand disease in a meta-analysis of high-quality epidemiologic prevalence studies."⁴

Prioritizing initial steps

Acute uterine bleeding can range from modestly heavy menstrual flow all the way to excessive HMB associated with hypovolemic shock. If a patient is hemodynamically unstable, the initial steps are to:

• Establish appropriate IV lines and arrange for urgent cross matching of blood.
• Concurrently, do a pelvic examination thorough enough to confirm that the bleeding is indeed coming from the uterus.
• Perform a bimanual pelvic examination, even though your findings must be tempered by an awareness of its limitations; typically lesions such as subserosal myomas don't cause bleeding on the one hand, while submucosal fibroids that can contribute to AUB cannot be detected manually, on the other.
• Lose no time in obtaining a urine or serum hCG assay for pregnancy. For patients who take anticoagulants, measure INR and other appropriate measures of coagulation function.

OF WHAT VALUE IS histologic evaluation of the endometrium at this juncture? While possibly desirable for select women who are at heightened risk for endometrial hyperplasia or cancer, the volume of blood present can interfere with obtaining an adequate specimen. Evaluating the structure of the endometrial cavity with sonographic or hysteroscopic imaging is always worthwhile for chronic AUB, but intrauterine blood and clotting can obscure the view. In the face of heavy menstrual bleeding, you can more easily perform adequate hysteroscopic imaging with a continuous flow system that efficiently evacuates intrauterine blood.⁵

That said, even such instruments can impede evaluation of the cavity when bleeding is heavy. As a result, indicated endometrial sampling or imaging of the endometrial cavity may have to wait until medical measures have successfully reduced or stopped the bleeding, or at the time of surgery if it is deemed necessary. Arteriovenous malformations cause bleeding that fails to respond to the usual measures. If you suspect such a lesion, color Doppler or magnetic resonance imaging are your best diagnostic choices.⁶

What are your medical options for acute AUB?

Before weighing any surgical options for acute AUB in nonpregnant women, first consider medical management. The exception would be if you suspect bleeding is coming from intrauterine lesions (aborting submucous leiomyomas, for example). Even if surgery seems inevitable, implementing a medical protocol while a patient is waiting for the operating room can reduce blood loss and might even preempt the need for surgery.

Estrogens

Although single-agent IV conjugated equine estrogens (CEE) have been shown to effectively treat acute uterine bleeding, the data are from only one randomized clinical trial. That published study shows giving IV CEE to be effective in nonpregnant women, without first doing a comprehensive assessment of the cause (via uterine imaging, for instance).⁷

Investigators treated hospitalized women with either 25 mg of IV CEE or placebo every 4 hours while quantifying bleeding volume by collecting all pads. At 5 hours, 72% of the treatment arm and 38% of the placebo arm had stopped bleeding. Unfortunately, the study wasn't designed to gauge any added benefit from continued dosing in the treatment group. CEE's mechanism of action in this circumstance is not clear, but it might not be specific to the endometrium itself, given reports of successful gonadal steroid regimens in the gastrointestinal and otolaryngology literature.^8,9

TO STOP THE BLEEDING, you may need to continue this regimen for up to 24 hours. Once bleeding stops, patients are usually converted to monophasic, multidose, oral contraceptives or moderate-to-high-dose progestins. No published data exist to determine the most effective approach, however. As a result, once we've stopped or substantially reduced the acute bleeding, we tend to convert these patients to one or another of the orally-based regimens described below.

Estrogens plus progestins

Notwithstanding a paucity of evidence, combination oral contraceptives (COCs), which are FDA-approved only for the indication of contraception, are often used off-label to treat acute AUB. Until recently, only low-quality evidence from textbooks and monographs supported this practice.¹⁰ But a recent clinical trial at our institution suggested that multidose, monophasic oral contraceptives may be effective for acute uterine bleeding.¹¹ In this pilot RCT, with a modest sample size, a COC with 35 ?g of EE and 1 mg of norethindrone appeared to be just as effective as a progestin-only regimen. Bleeding stopped in a median of 3 days with the COC given three times a day for 1 week and subse-quently every day for 3 weeks.

Progestins

The evidence evaluating oral medroxypro-gesterone acetate (MPA) for treating acute HMB is also limited, but encouraging, particularly for women who have added risks associated with estrogen-based regimens. (Again, keep in mind that suggested dosages and duration of progestins represent an off-label use.) Current evidence on the effectiveness of single-agent progestins is limited to MPA.

The first published series involved 24 adolescents who were hospitalized with excessive uterine bleeding and anemia. Oral MPA was begun with a loading dose of 60 to 120 mg on the first day, then 20 mg per day for the next 10 days.¹² Bleeding stopped in all the young women; 25% stopped bleeding within the first 24 hours; while the others had all done so by day 4.

In our institution's RCT, we gave 60 mg of MPA in three divided doses for week 1, after which we lowered the dose to 20 mg per day for the next 3 weeks.¹¹ Following this regimen, bleeding stopped within 3 days (on average) of when treatment began, no patients required surgery, and the women were quite pleased with their treatment.

GIVEN THE ABSENCE OF CLINICAL TRIALS, or even case series evaluating other progestins, it's difficult to know their relative effectiveness compared with MPA. The effectiveness of norethindrone in trials of heavy menstrual bleeding suggests that this would be the most likely second-line agent. Keep in mind that although Table 1 gives suggested dosing, it's based on clinical experience rather than controlled trials. Given the frequent association of depot MPA with AUB, it seems prudent to recommend against using MPA for treating acute uterine bleeding.

Other agents

There is high-quality evidence showing antifibrinolytics-especially tranexamic acid-to be effective for treating chronic idiopathic HMB. No studies have assessed the efficacy of these drugs, however, for specifically treating acute HMB. Nevertheless, and particularly in individuals with disorders of hemostasis, there may be a role for parenteral antifibrinolytic agents. The only one available in the United States is epsilon aminocaproic acid (Amicar), which can be initiated with a loading dose of 4 to 5 g IV, then continued with an IV infusion of 1 g per hour until bleeding stops. (Its use for this indication is also off-label.)

When it comes to GnRH agonists for managing acute AUB, once again, there are no published data evaluating a potential role, even though, for chronic AUB, such agents might help to establish amenorrhea. That would allow clinicians to replenish iron stores and create an appropriate plan of care.

BE CAREFUL, though, when giving GnRH agonists (GnRHa) to women who are anemic to watch out for the estradiol "flare" that follows induction of GnRHa. Lasting from about day 5 to day 14, the flare is often accompanied by uterine bleeding that's frequently heavy. For that reason, whenever using GnRHa, accompany them with about 3 weeks of a progestin-containing formulation such as MPA (10-20 mg twice daily) or a combination oral or transdermal contraceptive for the same 3 weeks.

When is surgery for acute AUB appropriate?

Although surgery should not be your first choice for treating most women with acute AUB, it may be more appropriate in certain patients: for women who are hemodynamically unstable, patients who do not respond to drugs, or those known to have intracavitary lesions (aborting myomas).

Dilatation and curretage (with hysteroscopy)

Even given such sparse data supporting a role for dilation and curettage (D&C) in managing acute uterine bleeding, clinicians usually perceive it to be effective. Don't forget that, for women with chronic AUB, the cycles that follow a successful D&C are similar to those that were present prior to curettage.¹³ Consequently, D&C per se has no demonstrated role in chronic AUB, particularly because it misses lesions that may contribute to or actually cause either the acute or chronic bleeding. As a result, should you deem D&C necessary for managing acute uterine bleeding, be sure to perform concomitant hysteroscopy.

Intracavitary tamponade

A simple approach, intrauterine tamponade can be used in an emergency room or even an office setting. An inflated, intracavitary Foley catheter balloon has been shown effective in many case reports and in one series of 20 patients, 17 of whom were successfully treated.¹⁴ Inflated ini-tially to 30 to 50 mL, the balloon stays inflated for 2 to 48 hours, based on factors such as what is thought to be triggering the bleeding. Once again, there's no evidence available to guide the clinician using intracavitary tamponade in the subsequent or concomitant use of medications such as gonadal steroids.

Endometrial ablation

Many case reports or short series describe endometrial ablation performed either under direct vision with a resectoscope, or with nonresectoscopic techniques (a.k.a. resectoscopic endometrial ablation or REA).^15-16 Most of these investigators describe heroic therapy in patients with substantial comorbidity, who either did not respond to drugs, were contraindicated from such approaches, or who were at high risk for surgery, such as hysterectomy. The obvious concern about performing endometrial ablation on women with inadequately evaluated endometrial cavities is the potential for obscuring the diagnosis of a uterine malignancy. As a result, be cautious about performing these techniques on a patient whose endometrial cavity has not been completely evaluated.

Uterine artery embolization and occlusion

Uterine artery embolization (UAE) is often used to treat obstetric hemorrhage, cervical ectopic pregnancies, and postoperative bleeding. How-ever, when it comes to acute uterine bleeding, there's a scarcity of reports in the literature evaluating UAE.¹⁷ Despite this lack of evidence, you should consider this option at least for women with acute HMB who've failed medical therapy but may not tolerate surgery or who ask to preserve their uterus.

An alternative to embolization may be uterine artery occlusion. Anecdotal reports exist of successful treatment of AUB with vaginal compression of the uterine arteries with ring forceps. Based on this information, a Doppler-guided clamp was developed that promises to be available soon to assist clinicians by targeting the uterine artery flow and then confirming that the vessel is compressed when the flow stops.

Total or supracervical hysterectomy

In managing acute uterine bleeding, total or supracervical hysterectomy is generally viewed as a last resort. Options for performing it are via laparotomy, vaginally, or under laparoscopic direction.

IN SUMMARY, nongestational acute uterine bleeding challenges ob/gyns and taxes health-care resources. Limited evidence suggests that there are many medical and simple procedures that can be effective without requiring an operating room. Even for those patients who appear to be headed for surgery, medical treatment may reduce blood loss while awaiting surgery and, if successful, could obviate the need for surgery altogether.

After interventions have successfully managed the acute phase, be sure to pay attention to evaluating and managing any underlying chronic AUB process. Such an approach, especially if augmented by appropriate iron therapy, may prevent the acute problem from recurring.

DR. MUNRO is Clinical Professor, Departments of Obstetrics and Gynecology, David Geffen School of Medicine at University of California, Los Angeles, and The Keck School of Medicine, University of Southern California. He is also Director of Gynecologic Services, Kaiser Permanente, Los Angeles Medical Center, and Chair, AUB Working Group, Southern California Permanente Medical Group, Los Angeles, CA.

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