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Evaluation and management of unscheduled bleeding in individuals using hormonal contraception

Evaluation and management of unscheduled bleeding in individuals using hormonal contraception
Literature review current through: Jan 2024.
This topic last updated: Apr 26, 2023.

INTRODUCTION — Unscheduled uterine bleeding is a frequent side effect with many contraceptives and a common reason patients choose to discontinue their contraceptives. The frequency of unscheduled bleeding is highest in the first few months of use and then begins to diminish for most, but not all, methods. Interventions that prevent or treat unscheduled bleeding could improve contraceptive acceptability and increase compliance and thus lead to fewer unplanned pregnancies.

This topic will discuss the evaluation of patients with unscheduled bleeding, our approach to treatment, and the various treatment options. Related content on the selection of a contraceptive method is presented separately.

(See "Contraception: Counseling and selection".)

In this topic, we will use the term "women" or "patient" to describe those who use female contraceptive methods. However, we recognize that not all people capable of pregnancy identify as women, and we encourage the reader to consider the specific counseling needs of transgender and gender nonbinary individuals. Clinicians should ask all patients who identify as male about their contraceptive needs as well.

DESCRIPTION OF BLEEDING PATTERNS — The following terminology has been suggested in contraceptive trials to standardize the description of patients with bleeding related to contraceptive use [1]:

Bleeding – Blood loss that requires the use of a tampon, pad, or panty liner.

Spotting – Minimal blood loss that does not require use of any type of protection.

Episode of bleeding/spotting – Bleeding/spotting days bounded on either end by two days of no bleeding or spotting.

Scheduled bleeding or withdrawal bleeding – Any bleeding or spotting that occurs during contraceptive hormone-free intervals; bleeding may continue through days 1 to 4 of the subsequent active cycle.

Unscheduled bleeding and unscheduled spotting – Any bleeding that occurs while taking active contraceptive hormones, except bleeding that begins in the hormone-free interval and continues through days 1 to 4 of the subsequent active cycle.

MECHANISM — The pathogenesis of unscheduled bleeding in patients using hormonal contraception is poorly understood [2]. Upon initiation of the method, unscheduled bleeding is thought to be due to a relatively thick endometrium transitioning to a relatively thin endometrium as a result of the dominant progestin component of all hormonal contraceptives [3]. With continuing use, it is thought to be the final step in a complex process activated by continuous exposure to exogenous sex steroids, particularly progestins [4]. In this environment, the endometrium develops a dense network of small, thin-walled, dilated, superficial veins and capillaries, which are fragile and prone to focal bleeding. The fragility of these vessels is due to alterations in their basement membranes and pericytes, as well as reduced structural support from the endometrial stroma and glands, which are also altered [5,6]. Altered matrix metalloproteinase activity appears to have a major role in this remodeling. Changes in endometrial perfusion, local vascular hemostasis, pro- and antioxidant processes, and migratory cells also appear to play a role [7,8].

CLINICAL SIGNIFICANCE — While not medically dangerous, unscheduled bleeding is a common reason for discontinuation of the contraceptive method [9-12]. In a survey study of over 6700 United States women, 46 percent of women had stopped at least one contraceptive method because they were unsatisfied with it [10]. The main clinical significance is that the patient is then at risk for unintended pregnancy if another contraceptive method is not begun. In the United States, it is estimated that nearly one-half of all pregnancies are unintended [13,14]. The roles of education and reassurance are discussed in detail below. (See 'Initial management' below.)

EVALUATION — Before assuming that unscheduled bleeding is result of hormonal contraception, the clinician must exclude identifiable pathology, as discussed below.

Indications for additional evaluation — Patients with severe pathology of the reproductive tract typically present with symptoms in addition to unscheduled bleeding. Common findings that accompany vaginal bleeding are cervicitis, cervical polyps, and uterine fibroids or polyps [15-17]. Patients who have pelvic inflammatory disease (PID; cervical motion tenderness OR uterine tenderness OR adnexal tenderness) in addition to cervicitis should be evaluated and treated appropriately. Women with erosive cervical lesions suggestive of cancer should be further evaluated with cervical biopsy and referral to a gynecologic oncologist, as needed. If a patient develops heavy or prolonged bleeding, or a significant change in bleeding pattern, and endometrial cancer is suspected, endometrial biopsy is indicated.

These diagnoses and evaluation of these entities are presented in detail in separate topic reviews.

(See "Acute cervicitis".)

(See "Benign cervical lesions and congenital anomalies of the cervix".)

(See "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history".)

(See "Endometrial polyps".)

(See "Pelvic inflammatory disease: Clinical manifestations and diagnosis".)

(See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis".)

Exclude pregnancy — Even with the most effective contraceptive methods, pregnancy should be considered and excluded if a patient experiences a significant change in her bleeding pattern or if she develops pregnancy-type symptoms (breast tenderness, nausea, urinary frequency, fatigue). Pregnancy (intrauterine and ectopic) and hormonal contraceptives cause many of the same signs and symptoms. Absence of uterine bleeding and unscheduled bleeding are not only signs of early pregnancy but also common occurrences with hormonal methods of birth control, both combined and progestin-only. Pregnancy should always be excluded in patients with abrupt onset of amenorrhea, signs and symptoms of pregnancy, and inconsistent or incorrect contraceptive use.

Questions to evaluate unscheduled bleeding — In addition to a full medical history, the following questions can help guide further evaluation when a patient is experiencing unscheduled bleeding or spotting:

What are the patient's main concerns? If bleeding is not bothersome, reassurance may be all that is needed.

What was her bleeding pattern prior to her current method of contraception? How has it changed?

How many days does she bleed each month, how heavy is the bleeding, and how many bleeding episodes occur? These questions assess the magnitude of the problem and impact on the patient's quality of life.

Does the bleeding occur during or after sex or is it associated with pain or urinary symptoms? Bleeding associated with sex, pain, or urinary symptoms is unlikely to be related to contraception.

What drugs or medications is she taking? Some drugs may affect bleeding patterns in contraceptive users [18].

Has she been consistent in her use of contraception? Missing pills or taking them late affects hormone levels, which can cause unscheduled bleeding.

Does she smoke? Smoking may affect bleeding patterns in contraceptive users [19].

Has she had a new partner or is she at increased risk of a sexually transmitted infection? Cervicitis and PID can cause unscheduled bleeding. (See "Acute cervicitis" and "Pelvic inflammatory disease: Clinical manifestations and diagnosis".)

When was her last cervical cancer screening? (See "Screening for cervical cancer in resource-rich settings".)

Beyond pregnancy testing, the decision to initiate a more detailed evaluation will depend on the answers to these questions and the type of contraceptive the patient is using. Unscheduled bleeding is common and expected with the use of progestin-only methods (contraceptive implants, progestin-only pills, depot medroxyprogesterone acetate, and the levonorgestrel-releasing intrauterine device [IUD]); further evaluation is not necessary unless indicated based on history (bleeding pattern was abnormal prior to contraceptive use), symptoms (menorrhagia, pain, vaginal discharge), or national cervical cancer screening guidelines, even if the unscheduled bleeding persists for the duration of contraceptive use. With the initiation of other contraceptive methods, including combined estrogen-progestin methods (pill, patch, ring) and the copper-releasing IUD, unscheduled bleeding is common and usually resolves over time; thus, further evaluation is not routinely necessary in the first six months of use.

Physical examination — A pelvic examination, both speculum and bimanual, is performed to exclude other reasons for unscheduled bleeding, including presence of cervical ectropion in users of combined estrogen-progestin contraceptives, infection (vaginitis, cervicitis, or PID), cervical malignancy, or trauma. Cervical cancer and sexually transmitted infection screening should be performed according to national screening guidelines. (See "Screening for cervical cancer in resource-rich settings" and "Screening for sexually transmitted infections".)

Imaging and laboratory testing — Depending on the findings and her symptoms, a pelvic ultrasound may be helpful to evaluate for possible uterine pathology (eg, fibroid, polyp). An endometrial biopsy is reasonable in patients over the age of 35 who had abnormal uterine bleeding for more than three months prior to starting contraception, patients with a history of endometrial hyperplasia, or patients with prolonged periods of unopposed estrogen stimulation secondary to chronic anovulation. Otherwise, the decision to biopsy the endometrium for patients who are experiencing unscheduled bleeding while using contraception will depend on the method they are using. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis".)

INITIAL MANAGEMENT — For patients in whom unscheduled bleeding is determined to be a result of their contraceptive, initial management includes counseling, a trial of observation if acceptable to the patient, and a trial of nonsteroidal anti-inflammatory drugs (NSAIDs) for those who prefer an intervention (algorithm 1). These suggestions are based mainly on our clinical experience, as the available data are limited.

Importance of counseling – Dissatisfaction with unpredictable uterine bleeding is a common reason patients choose to discontinue hormonal contraception [3,10]. Prior to initiating contraception, patients should be thoroughly counseled about the range of bleeding patterns associated with various contraceptive options and informed that there is no evidence that unscheduled bleeding is associated with decreased contraceptive efficacy or other harmful effects. The frequency of unscheduled bleeding is highest in the first few months of use and then begins to diminish. Providing this information as a component of standard contraceptive counseling helps patients choose the method that best suits their needs. If warned of the frequency, course, and significance of unscheduled bleeding, they may be more willing to adhere to the method if bleeding irregularities occur. If they are reassured that the method is effective despite their bleeding, they will be less likely to abandon the method and risk unintended pregnancy.

The unscheduled bleeding that occurs with contraceptive use is not associated with decreased contraceptive effectiveness unless bleeding is the result of nonadherence to the method (eg, missed pills). Users of short-acting hormonal methods, like oral contraceptive pills, the contraceptive patch, or the vaginal ring, should understand that missed or delayed ingestion, application, or placement can lead to unscheduled withdrawal bleeding. As an example, inconsistent pill use is associated with a 60 to 70 percent increase in the relative risk of unscheduled bleeding [20]. For these patients, we reinforce the importance of consistent use (reducing the number of missed doses, taking the pill at the same time each day) to improve the bleeding pattern [17,20]. Although supporting data are limited, computer or phone-based applications (apps) may provide helpful reminders for some patients [21].

Amenorrhea related to use of hormonal contraception does not require medical treatment. We reassure patients that amenorrhea is not a sign of reduced contraceptive efficacy nor is it dangerous to the patient. Patients who are at risk for pregnancy because of inconsistent contraceptive use should take a pregnancy test. (See 'Exclude pregnancy' above.)

Trial of observation – As discussed in the bullet above, the frequency of unscheduled bleeding is highest in the first few months of use. Thus, for patients who are otherwise low risk and comfortable with a trial of waiting, observation combined with consistent and correct use of the contraceptive method is a reasonable first step.

Trial of NSAIDs – Despite reassurance, some patients desire an active intervention to reduce unscheduled bleeding. While supporting data for the use of NSAIDs in this clinical situation are limited, NSAIDs are generally well tolerated, low risk, easily available, and low cost. Therefore, in patients who tolerate NSAIDs and desire a treatment course, we prescribe ibuprofen 400 to 800 mg three times a day for 5 to 10 days. This drug is more readily available and less expensive than those studied (celecoxib and mefenamic acid). Data specific to NSAID use in patients with progestin-only implants are discussed below. (See 'Management' below.)

Potential role of smoking cessation – Smokers are more likely than nonsmokers to experience unscheduled bleeding and spotting when taking estrogen-progestin contraceptive pills [17,22]. Bleeding is also more likely to persist through subsequent cycles [17]. Smoking cessation may result in improved cycle control and has other major health benefits [3]. We counsel all smokers about the options for smoking cessation. (See "Overview of smoking cessation management in adults".)

TREATMENTS FOR CONTINUED BOTHERSOME BLEEDING

Our approach — For women who continue to have bothersome, persistent unscheduled bleeding, we again exclude gynecologic disease and pregnancy (see 'Evaluation' above). Once the contraceptive method is confirmed as the likely cause of unscheduled bleeding, we treat patients as summarized in the figure (algorithm 1). These suggestions are based mainly on our clinical experience, as data are limited. We are generally in agreement with the Centers for Disease Control and Prevention (CDC) United States Selected Practice Recommendations (US SPR) for Contraceptive Use, 2016 (algorithm 2) [23]. The US SPR include information for providers regarding how contraceptive methods can be used and provide clinical guidance including information on the management and treatment of breakthrough bleeding.

As presented in the algorithm, our choice of treatment for unscheduled bleeding is based on the contraceptive method (table 1). We start with therapies for which there is the best evidence and then move, as needed, to therapies with less evidence to support them. Whether the medical therapies discussed below result in a statistically significant reduction in symptoms is unclear because most trials have been small and/or had design flaws.

Estrogen-progestin contraceptives

Bleeding pattern — Combined estrogen-progestin contraceptives include oral contraceptive pills (OCs), the transdermal contraceptive patch, and the vaginal contraceptive ring. An injectable combined estrogen-progestin contraceptive (Cyclofemina, Lunelle) is available in some countries.

Estrogen-progestin contraceptive pills – Unscheduled bleeding occurs in up to 50 percent of patients initiating cyclic OCs but decreases to less than 10 percent by the third month of use [3,17]. Randomized trials have reported that unscheduled bleeding is slightly higher with the lowest dose OCs (20 mcg ethinyl estradiol [EE] component) than with 30 to 35 mcg EE pills [24-26]. There is no evidence that unscheduled bleeding is associated with decreased efficacy, even with the lowest dose products, as long as patients take their pills consistently (ie, no missed days and at the same time every day) [3]. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".)

Continuous use of OCs involves taking hormonally active pills daily and indefinitely without an induced withdrawal bleed. Extended use involves taking hormonally active pills daily for intervals of several months, thus minimizing scheduled bleeds to only a few times per year. Compared with the traditional monthly regimen, continuous and extended use of OCs decreases the overall number of scheduled bleeding days; however, they are associated with a high frequency of unscheduled bleeding and spotting, particularly during the first three months of use [27-30]. In trials, absence of all uterine bleeding and spotting during months 0 to 3 was achieved in less than 50 percent of continuous OC users, but this rate increased to 80 to 90 percent by months 10 to 12 [27-29]. The duration of unscheduled bleeding appears to be higher in patients using continuous OCs that contain levonorgestrel (LNG) than in those that contain norethindrone acetate [31]. (See "Hormonal contraception for menstrual suppression".)

Patch and ring – The frequency of unscheduled bleeding upon initiation of the contraceptive patch and ring is generally similar to that with OCs. Neither are approved for extended or continuous use, but a randomized trial comparing extended versus cyclic vaginal ring regimens reported that skipping the hormone-free interval increased unscheduled bleeding and reduced the amount of scheduled/withdrawal bleeding [32]. Further information on the use and bleeding patterns of the contraceptive vaginal ring and transdermal patch is presented elsewhere.

(See "Contraception: Hormonal contraceptive vaginal rings".)

(See "Contraception: Transdermal contraceptive patches".)

Management — Once the contraceptive method is confirmed as the likely cause, we take the approaches below based on the dosing regimen of the estrogen-progestin contraceptive.

Women using a cyclic regimen — The optimal approach to treating women with persistent unscheduled bleeding from cyclic estrogen-progestin regimens is not known. For women who continue to have bothersome bleeding despite initial observation and/or a nonsteroidal anti-inflammatory drug (NSAID) trial, we proceed through the treatments in the order below.

Trial of vaginal contraceptive ring – For women who are having unscheduled bleeding with cyclic use of the combined estrogen-progestin pills and difficulty remembering to take a pill daily, another treatment option is to switch the patient to the estrogen-progestin vaginal ring (and stop the pill). Theoretically, this approach has two potential benefits: the patient is less likely to have unscheduled bleeding related to a "missed pill," and the vaginal ring is associated with more constant hormone levels than OCs. Although there are no studies evaluating this approach, the resulting elimination of wide swings in serum estrogen and progestin concentrations may reduce bothersome unscheduled bleeding. The ring has excellent cycle control under normal circumstances; however, this may not be the case in patients experiencing unscheduled bleeding.

Trial of different oral contraceptive formulation or dose – For patients using estrogen-progestin pills, changing the formulation (ie, type of estrogen or progestin) or dose has been proposed. Although supporting data are limited, such a change is reasonable, particularly if the patient requests another OC product. Allowing her to switch is unlikely to worsen bleeding patterns and can improve overall satisfaction with OC use. Since most comparative studies report that women on OCs containing ≤20 mcg estrogen have more unscheduled bleeding, it makes sense to first switch to an OC with a higher estrogen dose (not to exceed 35 mcg of estrogen) [26]. There is less evidence for changing the progestin, but that is also an option (table 2 and table 3) [33].

There is no evidence that monophasic OCs are associated with less unscheduled bleeding than phased OCs or that discontinuation due to dissatisfaction with bleeding patterns is different, but some studies have reported a lower incidence of unscheduled bleeding with triphasic rather than monophasic OCs [34-37]. There is also no evidence that pill products by different manufacturers, generic formulations, or different formulations of estrogen or progestin result in improved bleeding patterns [17]. Although uncontrolled studies have reported decreased bleeding after changing formulations, bleeding likely would have stopped with continued use of the initial OC regardless of the type of product used [3]. Patients who use a 21-day estrogen-progestin pill may have fewer unscheduled days of bleeding than patients using a 24-day regimen, although data are conflicting [38,39]. Of note, the total days of bleeding (scheduled plus unscheduled) will be higher for patients using a 21-day estrogen-progestin pill compared with 24-day regimen (mean 15.8 versus 13.2 days) [38]. Doubling or tripling the daily dose of OCs is not recommended to decrease unscheduled bleeding. While it may work for some patients, it has not been studied and may increase the risk of adverse events, such as thromboembolism. The authors do not provide supplemental estrogen-only as supporting data are lacking.

Women using continuous or extended regimens — In most patients, unscheduled bleeding will decrease over time with continuous or extended use of the estrogen-progestin pill or vaginal ring. We do not advise continuous or extended use of the transdermal patch because of theoretical concerns for increased risk of thromboembolism. (See "Contraception: Transdermal contraceptive patches", section on 'Risk of venous thrombotic events' and "Contraception: Transdermal contraceptive patches", section on 'Extended cycle use'.)

Hormone-free trial – For patients who develop bothersome unscheduled bleeding with continuous or extended use of the combined estrogen-progestin pill or ring, we and other experts advise stopping the product for three to four consecutive days [23,40]. This hormone-free interval does not lessen contraceptive efficacy as long as it is done after the first 21 days of hormone use.

We begin with a trial of a hormone-free interval because it is easy for a patient to stop and restart a product that she already has and there are limited trial data to support this approach [41]. The use of a three to four day hormone-free interval can be repeated whenever bothersome breakthrough bleeding occurs, as long as the patient has had at least 21 days of active pills before taking a hormone-free break. Over time, breakthrough bleeding episodes will become spaced out and stop. As an example, in one study where subjects were given the option of stopping the OC for four days if they had taken at least 24 days of active pills, the mean number of days of bleeding/spotting decreased from 19 days in the first 3 months of the study to 10 days in months 9 to 12 [42]. This technique should not be used more frequently than every three weeks in order to maintain contraceptive effectiveness. Data comparing a hormone-free interval with a change in product, discussed below, are not available.

Change in dose or formulation – For patients who continue to experience problematic unscheduled bleeding, we next offer a different OC because estrogen dose and progestin type appear to play a role in the amount of unscheduled bleeding patients experience when they start a continuous or extended method. In one trial, use of an OC pill containing 30 mcg of EE during the first year of use resulted in significantly less unscheduled bleeding than a pill containing 20 mcg of EE (35.5 versus 47.4 percent) [43]. In another trial, continuous use of OCs containing norethindrone acetate resulted in significantly more bleeding-free days than use of pills containing LNG [31]. The LNG dose (90 versus 100 mcg) does not seem to make a difference [44].

Progestin-only contraceptives

Depot medroxyprogesterone acetate

Bleeding types — Menstrual changes occur in most patients using depot medroxyprogesterone acetate (DMPA; subcutaneous or intramuscular formulations) [3,45]. Amenorrhea occurs in 12 percent of patients during the first three months of use, but by one year, 46 percent of users will be amenorrheic [3,46]. Although bleeding is rarely heavy, 25 percent of users will discontinue DMPA in the first year because of dissatisfaction with bleeding patterns [47]. Structured counseling prior to DMPA use increases continuation rates at one year of use and decreases discontinuation due to unscheduled bleeding. With continued use, the most common bleeding pattern is no bleeding; absence of all bleeding and spotting after one and five years of use is 50 and 80 percent, respectively [48-50]. Therefore, patients who are uncomfortable with cessation of uterine bleeding should be advised to use another method. (See "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration".)

The etiology of unscheduled bleeding in DMPA users is not clearly understood. Based on endometrial biopsy studies, atrophy and chronic endometritis appear to play a role [3,51]. Biopsy studies also suggest that the endometritis is related to atrophic endometrium rather than an infectious process [52].

Treatment options — Since the frequency and duration of unscheduled bleeding decrease with continued administration of DMPA, many patients find it acceptable to wait for spontaneous resolution of the problem. For patients who want an intervention, medication may help with cessation of bleeding and spotting; however, there is no evidence to support routine use of this approach. For patients who desire therapy, we first offer an over-the-counter NSAID for five to seven days, as discussed above. (See 'Initial management' above.)

For patients who continue to experience bothersome bleeding, we offer the treatments presented in the order below:

Supplemental estrogen – For patients without contraindications to estrogen, we begin with a supplemental estrogen, either in a combined estrogen-progestin OC pill or as estrogen alone. Estrogen supplementation is thought to promote tissue repair and coagulation. The addition of estrogen alone does not affect the contraceptive efficacy of DMPA but does put the patient at risk for estrogen-related side effects [3]. Contraindications to estrogen therapy are reviewed elsewhere. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Candidates'.)

Combined estrogen-progestin pill – We prescribe a monophasic low-dose combined OC pill to treat unscheduled bleeding in DMPA users, which is consistent with the CDC's US SPR [23]. The patient is treated with 10 to 20 days of a combined estrogen-progestin OC pill containing 35 mcg of estrogen or less (table 2). There are no data supporting one combined OC over another for this indication. Although combined OCs have not been well studied as a treatment for unscheduled bleeding with DMPA use, their effects on irregular bleeding are hypothesized to be similar to estrogen supplementation alone in DMPA users. The authors prefer a monophasic combined OC pill to estrogen-only therapy (below) because reproductive-aged patients are more familiar with this medication and it is relatively easy to obtain and inexpensive.

Studies have not compared different progestin types or estrogen doses for the treatment of unscheduled bleeding with DMPA use. When used alone (not in implant or DMPA users), studies suggest bleeding patterns are similar with 20 versus 30 mcg EE or 90 versus 100 mcg LNG combined OC pills, though bleeding may be less with a norethindrone acetate pill than an LNG pill [31,44]. It is not known if these data apply to patients experiencing unscheduled bleeding with DMPA.

Estrogen only – Supplemental estrogen only (ie, not combined estrogen-progestin products) for prevention or treatment of active unscheduled bleeding in DMPA users appears to be helpful, but conflicting data exist. Trials have reported discordant findings, and some were flawed by high discontinuation rates by study participants [53-57]. If the patient has no contraindications to estrogen supplementation, 7 to 14 days of oral estrogen (1.25 mg conjugated estrogen or 2 mg of micronized estradiol) or transdermal estrogen (a patch releasing 0.1 mg estradiol/24 hours) can be used.

In the largest therapeutic trial of this approach, 278 DMPA users with unscheduled bleeding were assigned to receive either EE 50 mcg, estrone sulfate 2.5 mg, or placebo for 14 days [55]. Estrone worked no better than placebo while EE 50 mcg stopped bleeding, but it recurred after discontinuation of EE. However, 50 mcg EE pills are no longer advised for routine use because of increased risk for thromboembolic events. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism'.)

Mefenamic acid – Mefenamic acid is an NSAID that is commonly used to treat pain and reduce dysmenorrhea. We suggest use of NSAIDs for five to seven days as an option for treatment of unscheduled spotting or light bleeding, although data supporting efficacy are limited. Mefenamic acid (500 mg twice per day for five days) was reported to be effective in control of bleeding during the first week of DMPA use but was not statistically more effective than placebo by week 4 [58].

Tranexamic acid – Tranexamic acid is an antifibrinolytic used during operative procedures in patients with hemophilia and for patients with heavy menstrual bleeding. A placebo-controlled trial of 100 DMPA users with unscheduled bleeding reported that tranexamic acid 250 mg orally four times per day for five days was effective in halting bleeding [59]. The tranexamic acid group had a significantly higher percentage of subjects in whom unscheduled bleeding stopped during the first week of treatment (88 versus 8.2 percent with placebo) and during the four-week follow-up period (68 versus 0 percent with placebo). The mean number of bleeding/spotting days was also significantly different between the groups (5.7 versus 17.5 days). The cost of tranexamic acid varies by region and may be prohibitive in some areas.

Treatments with limited data

Prevention of unscheduled bleeding in new DMPA users – A few trials have studied use of supplemental estrogen for prevention of unscheduled bleeding in new DMPA users because unscheduled bleeding is especially common in this population and is the reason many patients do not return for a second injection. There is no high-quality evidence of efficacy, but some promising trends have been observed that require further study [53,56,57]. At this time, we do not advise prophylactic use of estrogen to prevent unscheduled bleeding in new DMPA users.

Shortening the interval between DMPA injections – Increasing the frequency of DMPA injections is another approach to treatment of unscheduled bleeding. Although widely used, there are no studies evaluating the efficacy of this practice. We do not suggest shortening the interval between DMPA injections to treat unscheduled bleeding.

Mifepristone – Although a promising approach, more data are needed on use of mifepristone in patients with unscheduled bleeding from DMPA. In one trial of 20 patients starting DMPA, treatment with 50 mg mifepristone reduced unscheduled bleeding during the first three months of use compared with placebo (15 versus 36 percent) [60]. One limitation for United States clinicians is that a low-dose formulation of mifepristone (50 mg) is not available. The 200 mg dose used for termination of pregnancy has not been studied in the context of patients with unscheduled bleeding from contraception, is not available by prescription, and is costly.

Doxycycline – In a double-blind placebo-controlled randomized trial in 68 DMPA users with a current bleeding episode, doxycycline 100 mg twice daily for five days was not more effective than placebo for stopping a current episode of bleeding or for improving bleeding characteristics in the three months following treatment [61].

Progestin-releasing implants — Several progestin-releasing, long-acting contraceptive implants are available. A single rod, 68 mg etonogestrel-releasing system (Nexplanon) is available in many countries. Outside the United States, a two rod, 150 mg LNG-releasing system (Jadelle or Sino-implant) is available for use. Although the use of a six rod, 216 mg LNG-releasing system (Norplant) was stopped in the United States in 2002, patients may present with these implants. (See "Contraception: Etonogestrel implant".)

Bleeding patterns — All progestin contraceptive implants are associated with alterations in uterine bleeding patterns, which can range from amenorrhea to frequent, unscheduled bleeding [54]. Over a three-month period, 78 percent of etonogestrel implant users reported some form of unscheduled bleeding [62-64]. Similarly, 75 to 80 percent of patients using the six rod LNG implant reported unpredictable bleeding patterns [54,65]. Amenorrhea may not be achieved or sustained with the progestin implants [63]. However, a favorable bleeding pattern within the first three months appears to predict a continued favorable pattern during the remainder of use, whereas those with unfavorable patterns have a 50 percent chance of improving [63].

One review reported that 6 to 23 percent of etonogestrel implant users worldwide discontinued the method because of bleeding issues [66].

Management — For patients with unscheduled bleeding related to progestin implants, our preference is expectant management rather than medical therapy. We begin with supportive counseling and reassurance that the bleeding is not dangerous and is likely to improve with time, typically in 6 to 12 months. However, some patients may find unscheduled bleeding bothersome enough to consider removal of the contraceptive implant. Before we remove a highly effective contraceptive, we offer patients medical therapy to minimize their symptoms.

There are no comparisons of the efficacy of the different treatment options for unscheduled bleeding, so the optimal treatment strategy is not known. Although the data are limited, we offer NSAIDs as initial therapy because they are inexpensive, well tolerated, and have few side effects. Unless contraindicated, we prescribe ibuprofen 400 to 800 mg three times a day for 5 to 10 days because this drug is more readily available and less expensive than those studied (celecoxib and mefenamic acid). If NSAID treatment does not improve the patient's symptoms, we the offer a trial of combined oral contraceptives (COCs), given in a cyclic fashion, for three to six months. The COCs can be used in conjunction with the NSAIDs for persistent bleeding. If none of these options resolve the bleeding, the patient may benefit from a different form of contraception. As discussed above, we exclude pregnancy prior to treating any symptoms. (See 'Evaluation' above.)

Studies evaluating the efficacy of different treatment options are discussed in the following sections.

Mefenamic acid or celecoxib – Compared with placebo, studies in patients with etonogestrel implants report decreased bleeding with mefenamic acid 500 mg orally three times daily or celecoxib 200 mg orally daily, for a total treatment of five to seven days [67,68]. It is less clear if NSAIDs also reduce irregular bleeding resulting from the LNG implant. While the initial pilot studies supported NSAID use in these patients, subsequent larger studies did not confirm these findings [54,69-71]. NSAID use is consistent with the US SPR that suggest a trial of NSAIDs to treat unscheduled bleeding in patients with the etonogestrel implant (there are no recommendations for LNG implants, which are not available in the United States) [23].

Combined estrogen-progestin oral contraceptive pills – Trials have reported decreased abnormal bleeding days in patients with LNG implants treated with COCs compared with placebo [72,73]. COCs can be used for 10 to 20 days in a trial to decrease bleeding [23]. Alternatively, patients may find it more convenient to cycle on COCs for one to three months to cause scheduled bleeding [3]. The authors typically treat the patient with one cycle of COCs and then reassess the symptoms. The number of days of scheduled bleeding may total more days than the unscheduled bleeding would have been, but patients tend to prefer scheduled to unscheduled bleeding. The authors prefer a monophasic COC pill to estrogen-only therapy (below) because reproductive-aged patients are more familiar with this medication and it is relatively easy to obtain and inexpensive. No one COC can be recommended over another for this indication, as studies have not compared different progestin types or estrogen doses for the treatment of unscheduled bleeding with etonogestrel implants.

Supplemental estrogen only – Another option for reducing irregular bleeding associated with progestin implants is estrogen-only therapy, which stabilizes the endometrial lining. Exogenous estrogen can be administered as a pill or transdermal therapy.

Most of the data on exogenous estrogen for treating unscheduled bleeding are from studies of the LNG implant. Trials of estrogen to treat unscheduled bleeding in patients with the etonogestrel implant have not been reported, but it is presumed that efficacy will be similar. The US SPR suggest a trial of combined estrogen-progestin oral contraceptives or estrogen-only therapy for patients with irregular bleeding resulting from the etonogestrel implant (there are no recommendations for LNG implants, which are not available in the United States) [23]. In general, we prescribe COC pills containing 35 mcg of estrogen or less, although the studies referenced in the US SPR used pills containing 50 mcg of estrogen. We do not use 50 mcg estrogen pills because of the increased risk of thromboembolic events.

Oral conjugated estrogen 1.25 mg or estradiol 2 mg – When administered once per day for seven days, these shorten episodes of unscheduled bleeding associated with the six rod LNG implant [69,72,73]. Use of these estrogens may also increase the interval between bleeding episodes [72].

Transdermal estrogen (estradiol 0.1 mg/day) – This estrogen form may improve unscheduled bleeding in patients with the LNG implant, but limited data do not suggest efficacy. In a trial of 64 patients with irregular bleeding treated with either transdermal estrogen or placebo, there was not a significant benefit to transdermal estrogen treatment [74].

Selective estrogen receptor modulator (tamoxifen 10 mg bid for seven days) – Two double-blind trials have found that seven day course of tamoxifen for LNG implant (6 rod) users experiencing frequent or prolonged bleeding or spotting reported less unscheduled bleeding and more days of amenorrhea over three months [75,76]. Tamoxifen appears to inhibit endometrial angiogenesis (vessel formation), which may help to offset the abnormal vessel development mediated by progestin exposure that likely results in unscheduled bleeding. Tamoxifen can increase the risk of thromboembolic events and should not be used in those with additional risk factors for thromboembolic events.

Other — Other therapies that have been tried are ineffective, less well studied, or not widely available. The progesterone receptor modulators ulipristal and mifepristone appear to reduce unscheduled bleeding in small trials, but data are limited. A trial including 65 patients using etonogestrel implants comparing ulipristal with placebo reported five fewer days of bleeding in the patients receiving ulipristal [77]. Serum progesterone levels were nonovulatory in a subset of patients. Low doses of mifepristone (50 to 100 mg) also appear to be effective in reducing unscheduled bleeding in six rod LNG implant and etonogestrel implant users [78-81]. Mifepristone, however, is not commercially available in these doses and theoretically may counteract the contraceptive efficacy of progestin implants.

Vitamin E and curcumin are ineffective [70,82]. Studies on progestin supplementation have been inconclusive [69]. Tranexamic acid, an antifibrinolytic, shows promise for six rod LNG implant users [83], and doxycycline shows promise for etonogestrel implant users [84], but results need to be confirmed with longer trials and longer periods of follow-up.

Progestin-only pills — Progestin-only pills (POPs) are taken every day without interruption. They have an unpredictable effect on ovulation. Approximately 40 to 50 percent of patients who use POPs continue to have cyclic withdrawal bleeding, 40 percent will have irregular cycles or spotting, and 10 percent will have amenorrhea [3]. Having the patient take the POP at the same time every day and eliminating missed doses will minimize the frequency of unscheduled bleeding. (See "Contraception: Progestin-only pills (POPs)".)

Many patients taking POPs do so because they cannot use or do not want estrogen therapy. For patients with bothersome unscheduled bleeding that does not improve with observation and/or NSAIDs, we next offer a trial of a different contraceptive method. For women who can tolerate estrogen, a trial of combined hormonal contraceptive is reasonable, although these women may prefer to just change methods rather than take both POPs and a combined hormonal contraceptive [85]. For women who are unable to take estrogen products, we advise a trial of observation, NSAIDs, and then a change in contraceptive method if unacceptable bleeding continues.

While low doses of mifepristone can decrease the number and duration of unscheduled bleeding episodes in POP users, especially in initial cycles, mifepristone is not readily available for this purpose [86]. (See 'Treatments with limited data' above.)

Intrauterine devices — Both copper and LNG-releasing intrauterine devices (IUDs) may cause changes in bleeding patterns, including heavier menses (primarily copper IUDs), intermenstrual spotting (both types), or amenorrhea (only LNG IUDs). Amenorrhea does not require treatment. For patients who desire treatment of unscheduled bleeding, we offer NSAID treatment with ibuprofen 400 mg, naproxen 250 mg, or mefenamic acid 500 mg three times per day for five to seven days. Small trials of tamoxifen and mifepristone in patients initiating the 52 mg LNG-releasing IUDs did not report reduced bleeding at three months compared with placebo [87,88]. A detailed discussion of evaluation and management of altered bleeding patterns with IUDs is presented separately. (See "Intrauterine contraception: Management of side effects and complications".)

RETURN OF NORMAL MENSES AFTER DISCONTINUATION — The patient's bleeding pattern should return to its pre-contraception pattern after discontinuation of the method. This can take as little as one cycle for estrogen-progestin contraceptives (pill, patch, ring) and most progestin-only methods (pill, implant, intrauterine device); however, it may take one year to 18 months in depot medroxyprogesterone acetate (DMPA) users. Except for DMPA, the bleeding pattern usually returns to its pre-contraception baseline within three months.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Contraception".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Hormonal methods of birth control (Beyond the Basics)" and "Patient education: Long-acting methods of birth control (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Description and significance – Scheduled bleeding describes any uterine bleeding or spotting that occurs during contraceptive hormone-free intervals and may extend for one to four days into the next active cycle. Unscheduled bleeding is that which occurs outside the planned hormone-free time window. Prior to initiating any contraceptive method, counseling about the frequency, course, and significance of uterine bleeding helps avoid patient dissatisfaction and method discontinuation. Method discontinuation potentially places the patient at risk for unintended pregnancy.

(See 'Description of bleeding patterns' above.)

(See 'Clinical significance' above.)

Evaluation to exclude identifiable causes – Before the clinician can assume that unscheduled bleeding is a result of hormonal contraception, pregnancy and identifiable pathology must be excluded. Common findings that can present with unscheduled vaginal bleeding include cervicitis, cervical polyps, and uterine fibroids or polyps. (See 'Evaluation' above.)

Initial management – Initial management includes counseling and a period of observation, as bleeding will often resolve. Our general approach to management of unscheduled bleeding is summarized in the figure (algorithm 1). Patients are reassured that unscheduled bleeding that occurs with contraceptive use is not associated with decreased contraceptive effectiveness unless bleeding is the result of nonadherence to the method (eg, missed pills). For patients who desire an active intervention, we offer a trial of over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs). (See 'Initial management' above.)

Continued bothersome bleeding – For patients who continue to have bothersome unscheduled bleeding, we again exclude gynecologic disease and pregnancy. Once the contraceptive method is reconfirmed as the likely cause of unscheduled bleeding, we treat patients as summarized in the figure (algorithm 1). These suggestions are based mainly on our clinical experience, as the available data are of limited quality. We are generally in agreement with that of the Centers for Disease Control and Prevention (CDC) United States Selected Practice Recommendations for Contraceptive Use, 2016 (algorithm 2). The approach is based on the specific contraceptive in use. (See 'Our approach' above.)

Combined estrogen-progestin contraception – Combined hormonal contraception includes oral pills, a transdermal patch, and vaginal contraceptive rings. Unscheduled bleeding occurs in up to 50 percent of patients initiating estrogen-progestin contraceptive pills but decreases to less than 10 percent by the third month of use. Taking the pills consistently and cessation of smoking may reduce unscheduled bleeding. (See 'Estrogen-progestin contraceptives' above.)

-For patients using cyclic dosing of the estrogen-progestin pill, patch, or ring, the optimal approach to treating persistent unscheduled bleeding is not known. We offer patients a trial of NSAIDs, the vaginal contraceptive ring (for patients taking cyclic pills), and a method with a different dose or formulation, in that order. (See 'Women using a cyclic regimen' above.)

-For patients using continuous or extended cycle regimens, most unscheduled bleeding will resolve over time. For patients who prefer an active intervention, limited data support a trial of a short hormone-free interval or changing to a different dose/formulation. Data comparing the two strategies are not available. We generally offer a trial of 3 to 4 hormone-free days, assuming the patient has already used the method for at least 21 days, because it is relatively easy to stop and restart a method that is already in use. (See 'Women using continuous or extended regimens' above.)

Depot medroxyprogesterone acetate (DMPA) – We consider a period of observation for DMPA users with unscheduled bleeding, as the bleeding episodes will usually decrease over time. For those who desire an active intervention beyond NSAIDs, we offer a trial of supplemental estrogen, mefenamic acid, and tranexamic acid, in that order. (See 'Treatment options' above.)

Progestin-only implants – Patients using progestin-releasing implants are counseled that irregular bleeding is a common side effect, is not dangerous, and frequently improves during the first year of use. For patients who desire treatment of unscheduled bleeding, we offer a trial of NSAID therapy and then supplemental estrogen. (See 'Management' above.)

Progestin-only pills (POPs) – We counsel patients that POPs should be taken at the same time each day to minimize unscheduled bleeding. For patients with persistent bothersome bleeding, we suggest switching to another method, although estrogen supplementation may be reasonable for some patients. (See 'Progestin-only pills' above.)

Intrauterine device (IUD) – For patients who desire treatment of unscheduled bleeding related to intrauterine contraception, we offer NSAID treatment with ibuprofen 400 mg, naproxen 250 mg, or mefenamic acid 500 mg three times per day for five to seven days. (See 'Intrauterine devices' above.)

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Topic 5474 Version 50.0

References

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