Therapeutic Options for

Unscheduled Bleeding
Associated with Long-Acting
Reversible Contraception
EmmaKate Friedlander, MD*, Bliss Kaneshiro, MD, MPH

KEYWORDS
 Irregular bleeding  Intrauterine device  Contraceptive implant  Levonorgestrel
 Etonogestrel

KEY POINTS
 Long-acting reversible contraception (LARCs), including intrauterine devices and
implants, are highly effective forms of birth control.
 Irregular vaginal bleeding is one of the most common reasons for premature discontinu-
ation of LARC devices.
 Nonsteroidal antiinflammatory drugs can decrease unscheduled bleeding associated with
LARC use and are the most well studied for this indication.
 Other medications that can decrease unscheduled bleeding include antifibrinolytics
(tranexamic acid), antiprogestins (mifepristone), and matrix metalloproteinase inhibitors
(doxycycline).

INTRODUCTION

Long-acting reversible contraception (LARC), such as intrauterine devices (IUDs)

and implants, are the most effective reversible contraceptives available.1 A common
side effect of both IUDs and implants is an alteration in menstrual bleeding patterns.
Women can experience heavier bleeding with the copper IUD or unscheduled
bleeding and spotting with the hormonal and copper IUD as well as the contraceptive
implant. Dissatisfaction with bleeding, particularly heavy or unscheduled bleeding and
spotting, is a common reason for early discontinuation of LARC methods.2 Therapies
that can prevent or treat unscheduled bleeding could improve patient satisfaction,
increase uptake of LARC methods, and reduce early discontinuation, all of which
would result in fewer unplanned pregnancies.

Family Planning Division, Department of Obstetrics, Gynecology and Women’s Health, Univer-
sity of Hawaii John A. Burns School of Medicine, 1319 Punahou Street, #824, Honolulu, HI
96826, USA
* Corresponding author.
E-mail address: [email protected]

Obstet Gynecol Clin N Am 42 (2015) 593–603

http://dx.doi.org/10.1016/j.ogc.2015.07.004 obgyn.theclinics.com
0889-8545/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
594 Friedlander & Kaneshiro

The reason women experience unscheduled bleeding with IUDs and implants has
not been clearly elucidated. Unscheduled bleeding falls into 2 categories: bleeding
that occurs with initiation of a LARC method and bleeding that occurs with prolonged
use of LARC. Bleeding that occurs with initiation of a levonorgestrel (LNG) IUD and
etonogestrel (ENG) implant is common and is most likely the result of the endome-
trium transitioning to a thin state from consistent progestin exposure. The precise
mechanism of unscheduled bleeding that occurs with prolonged exposure to pro-
gestin is unknown but is thought to be related to the progestin dilating superficial
veins and capillaries, which are fragile and susceptible to focal bleeding. Other po-
tential influences include changes in structural support in the endometrium, altered
matrix metalloproteinase (MMP) activity, and changes in endometrial perfusion and
hemostasis.
Structured direct counseling before LARC initiation to inform women about
common bleeding patterns associated with each contraceptive method is critical
to method initiation and acceptance. Emphasizing that unscheduled bleeding is not
associated with decreased efficacy of the method is key. Advance knowledge of
possible unscheduled bleeding may reassure users, that if bleeding irregularities
occur, the method is still effective; users may be willing to wait longer for unscheduled
bleeding or spotting to resolve.
Pregnancy should always be excluded first when new-onset amenorrhea is accom-
panied by signs or symptoms of pregnancy. If a woman with an IUD complains of both
irregular bleeding and pelvic pain, it is important to verify proper placement by
examination or ultrasound to ensure that the device is not in the cervix, embedded
in the myometrium, or perforated through the uterus. Consideration should also be
given to infections or pathologic causes like cervical or endometrial cancer. Cultures
or endometrial biopsies can be done with an IUD in place.
Heavy, prolonged, and unscheduled bleeding are strongly associated with dissatis-
faction and early discontinuation of LARC methods.3–6 Clinicians must, therefore, be
armed with evidence-based interventions to alleviate this common side effect. The
authors review the current literature related to the treatment of unscheduled bleeding
and spotting that accompanies IUD and contraceptive implant use, discuss major
themes in the treatment of unscheduled bleeding, and identify areas where further
research is needed. In the authors’ review of the literature, they limited their search
to human subjects and articles published in English. The authors excluded treatment
modalities that are not available in the United States.

COPPER INTRAUTERINE DEVICE

With the copper IUD (copper T380A/Paragard [Teva Women’s Health, Inc, Sellersville,
PA, USA]), irregular spotting and prolonged or heavier menses are frequent in the first
few months of use. Menstrual bleeding can be increased up to 55% to 74%, which is
thought to be because of excessive prostaglandin release in the endometrial cavity.7,8
The discontinuation rate for pain or bleeding in one trial of the copper T380A was 5%
at 1 year, 8% at 2 years, and 9% at 3 years.9

Interventions for Heavy Bleeding

Treatments for heavy bleeding associated with copper IUD use include nonsteroidal
antiinflammatory drugs (NSAIDs), antifibrinolytic agents, and antidiuretics. Some trials
have also studied prophylactic interventions to prevent the initial increase in bleeding
known to occur for most users. Table 1 contains a summary of medical interventions
shown to have a benefit in clinical trials for heavy bleeding in copper IUD users.
 Therapeutic Options for Unscheduled Bleeding 595

Table 1
Medical interventions for heavy bleeding in copper IUD users

Length
Timing Medication Class Medication Dose Frequency of Time
Prophylaxis NSAID Ibuprofen 400 mg 3 Times daily 10 d
Antifibrinolytic Tranexamic acid 500 mg 2 Times daily 5d
Tranexamic acid 1000 mg 2 Times daily 5d
Treatment NSAID Ibuprofen 400 mg 4 Times daily 7d
Indomethacin 25 mg 2 Times daily 7d
Indomethacin 25 mg 4 Times daily 3d
Mefenamic acid 100 mg 3 Times daily 3d
Mefenamic acid 500 mg 3 Times daily 5d
Diclofenac 50 mg 3 Times daily 1 d, then
25 mg 3 Times daily 4d
Antifibrinolytic Tranexamic acid 1500 mg 3 Times daily 5d
Antidiuretic Desmopressin 300 mcg Intranasal daily 5d

Nonsteroidal antiinflammatory drugs

NSAIDs such as ibuprofen, indomethacin, mefenamic acid, and diclofenac are the
most widely studied for blood loss reduction in copper IUD users. NSAIDs inhibit pros-
taglandin synthesis and decrease endometrial prostaglandin release.
Exploring NSAIDs as a prophylactic measure, ibuprofen 400 mg was administered 3
times daily for 10 days with the first menses after IUD insertion in a randomized
controlled trial of 28 new copper IUD users with previously normal menses. Women
who received prophylactic ibuprofen had less menstrual blood loss compared with
women who received placebo (P<.05). When compared with preinsertion values,
blood loss increased by 74% in the placebo group and 2% in the ibuprofen group
(P<.01).7 This trial did not collect data on menses after stopping the intervention, so
it is unclear if the prophylactic treatment had a sustained effect or if benefits were
limited to the first cycle. Taking a prolonged course of ibuprofen with each menstrual
period may be impractical for many women.
As a treatment of heavy bleeding, ibuprofen 400 mg 4 times daily for 7 days initiated
on the first day of menses in copper IUD users decreased blood loss by 25% in one
trial (P<.05).10 Indomethacin 25 mg 4 times daily for 3 days with menses was also
associated with a significant reduction in blood loss of 38% (P<.01).11 Another trial
of indomethacin used 25 mg twice daily for 7 days initiated at the start of menses
in women who reported heavy or prolonged bleeding and noted a significant reduction
in the number of bleeding/spotting days (10 fewer days per 90-day cycle) as well as
length of bleeding episode (approximately 3 days less).12 Mefenamic acid 100 mg 3
times daily for 3 days, given several days before expected menstruation or with the
start of menses, was also associated with a significant reduction in blood loss
(P<.01).13 Higher doses of mefenamic acid, 500 mg 3 times daily for 5 days starting
with menses, were associated with a reduction in mean blood loss of 47.5%
(P<.001).14 Diclofenac sodium 50 mg 3 times daily for 1 day, followed by 25 mg 3 times
daily for 4 days decreased mean blood loss by 20%, though no change was seen in
pelvic pain or duration of menses.15
Aspirin is not recommended as a treatment of unscheduled bleeding. In one trial,
aspirin 1000 mg 3 times daily for 5 days starting with menses in women with a copper
IUD resulted in significantly increased menstrual bleeding in women whose baseline
mean blood loss was less than 60 mL (P<.05). Treatment was not associated with
596 Friedlander & Kaneshiro

significant changes in blood loss in women with a baseline mean blood loss of 60 to
80 mL or more than 80 mL.16
Antifibrinolytic agents
Antifibrinolytic agents, such as tranexamic acid, are thought to reduce heavy bleeding
by preventing the degradation of fibrin. Lin and colleagues17 compared bleeding with
first menses after copper IUD insertion when participants took prophylactic tranexamic
acid 500 mg or 1000 mg twice daily for 5 days versus placebo. All groups had an in-
crease in blood loss in the first cycle, which then decreased over subsequent cycles.
Both doses of tranexamic acid were associated with significantly less blood loss
(approximately 20 mL less) compared with placebo (P<.05). The higher dose of tranexa-
mic acid did not confer an additional benefit. Both tranexamic acid groups also had
significantly fewer participants with blood loss of more than 80 mL per cycle compared
with placebo. In another trial of therapeutic tranexamic acid, 1500 mg 3 times daily for
5 days with menses significantly decreased menstrual blood loss by 54% (P<.001),
though a change in pelvic pain intensity or duration of menses was not noted.15
Antidiuretics
Antidiuretics like desmopressin, a synthetic version of vasopressin, are theorized to
decrease heavy bleeding by acting as a vasoconstrictor. Desmopressin 300 mcg
intranasal daily for 5 days with menses led to a significant reduction in blood loss of
40.5% in a trial of women with menorrhagia associated with a copper IUD.14

Summary of Recommendations for Heavy Bleeding with the Copper Intrauterine

Device
For prophylaxis against heavy bleeding in new copper IUD users, consider ibuprofen
or tranexamic acid starting with the first day of menses. For treatment of heavy
bleeding once a copper IUD is in place, consider NSAIDs first, including ibuprofen,
indomethacin, mefenamic acid, and diclofenac, each started on the first day of
menses. Other promising interventions to treat heavy bleeding associated with the
copper IUD include tranexamic acid and desmopressin. Aspirin is not recommended.

LEVONORGESTREL INTRAUTERINE DEVICE

Overall, progestin-containing IUDs are associated with decreased menstrual bleeding

or amenorrhea. After 6 months, 44% of women using the LNG 20 (Mirena [Bayer
HealthCare Pharmaceuticals Inc, Wayne, NJ, USA]) (releases 20 mcg of LNG per
day) reported amenorrhea. This proportion increased to 50% after 12 and 24 months
of use.18 Increased intermenstrual bleeding and spotting are also commonly noted
with LNG 20 IUD use. Thirty-five percent of users experience frequent or prolonged
bleeding, defined as more than 4 episodes of bleeding in 90 days or one episode last-
ing more than 10 days, in the first 3 months of use. This proportion decreases to 4% by
1 year of use.8 The likelihood of improved bleeding over time is encouraging, yet the
discontinuation rate for menstrual disturbance is 5.9% and is the most frequently cited
reason for discontinuation.4
Similar bleeding patterns are seen with the LNG 14 IUD (Skyla) (releases 14 mcg of
LNG per day), though amenorrhea is less common. Unscheduled bleeding is common
in the first 3 months of use, with 59% of women reporting prolonged bleeding, 42%
reporting irregular bleeding, and 31% reporting frequent bleeding. These proportions
decrease to 9%, 23%, and 8%, respectively, at the end of 1 year. At 1 year, 6% of
women report amenorrhea, increasing to 12% at year 3. The discontinuation rate
for menstrual disturbance with the LNG 14 IUD is approximately 5%.3
 Therapeutic Options for Unscheduled Bleeding 597

Comprehensive structured counseling before LNG IUD insertion and reassurance

when unscheduled bleeding occurs is integral to a clinical practice that includes
IUD insertion. Historically, clinicians prescribed cyclic combined oral contraceptive
pills in addition to the IUD if bothersome unscheduled bleeding occurred. This
prescription provided endometrial stabilization with estrogen while maintaining the
superior contraceptive efficacy of the IUD. Although this was shown to be beneficial
in levonorgestrel implant (Norplant) users, no data currently support this practice
with the LNG IUD.

Treatment of Irregular Bleeding

Similar to copper IUD trials, interventions for irregular bleeding associated with the
LNG 20 IUD include NSAIDs (naproxen and mefenamic acid) and antifibrinolytic
agents (tranexamic acid). Other interventions studied include estrogen, antiprogestins
(mifepristone), and selective progesterone receptor modulators (SPRMs; like ulipristal
acetate). No interventions to decrease irregular bleeding with the LNG 14 IUD have
been studied to date. Table 2 contains a summary of medical interventions shown
to have a benefit in clinical trials for irregular bleeding in LNG IUD users.

Nonsteroidal antiinflammatory drugs

Naproxen 500 mg twice daily for 5 days, beginning the day after LNG 20 insertion and
repeated monthly for 3 cycles, was associated with a 10% decrease in bleeding and
spotting days. When the number of bleeding and spotting days were divided into quar-
tiles, the naproxen group was most likely to be in the lowest quartile when compared
with placebo (42.9% vs 16.3%; P 5 .03). However, 4 weeks after treatment, the effects
did not persist; no difference in bleeding or spotting days was noted.19
Mefenamic acid 500 mg 3 times daily was initiated in new LNG 20 users when they
had their first episode of bleeding or spotting, and treatment was continued until the
day after the episode stopped. No significant reduction in median bleeding/spotting
days when compared with placebo was seen.20

Antifibrinolytic agents
Tranexamic acid 500 mg 3 times daily was initiated in new LNG 20 IUD users when
they had their first episode of bleeding or spotting, and treatment was continued until
the day after the episode stopped. A reduction of 8 bleeding/spotting days over a
90-day period was noted (P 5 .049), but this was not significant after adjustment.20

Table 2
Efficacy of medical interventions for irregular bleeding/spotting in LNG IUD users

Dose
Medication Class Medication (mg) Frequency Length of Time
Decreased NSAID Naproxen 500 2 Times daily 5 d
bleeding Antifibrinolytic Tranexamic acid 500 3 Times daily Until bleeding
stops
Antiprogestin Mifepristone 100 Once Monthly
No effect on NSAID Mefenamic acid 500 3 Times daily Until bleeding
bleeding stops
Increased Estrogen Estradiol 0.1 Transdermal Changed weekly
bleeding SPRM Ulipristal acetate 50 Daily 3 d (Starting 21 d
after insertion)
598 Friedlander & Kaneshiro

Estrogen
Estradiol has been studied as a means to stimulate endometrial estrogen receptors,
with the goal of stabilizing the endometrial vasculature and epithelium. Clinical trials
demonstrate estrogen is not an effective treatment of unscheduled bleeding. The
estradiol 0.1-mg transdermal patch, beginning the day after LNG 20 IUD insertion
and changed weekly for 12 weeks, was associated with an increase in bleeding and
spotting days, with an adjusted relative risk of 1.25 (confidence interval 1.17–1.34).
When the number of bleeding and spotting days were divided into quartiles, the estra-
diol group was most likely to be in the highest quartile when compared with placebo
(40.9% vs 18.6%; P 5 .02). Four weeks after treatment, no difference in the number of
bleeding or spotting days was noted. Dissatisfaction scores were higher in the estra-
diol group, with 39.5% reporting dissatisfaction with their bleeding pattern in the first
4 weeks compared with 11.6% of the placebo group.19

Antiprogestins
Antiprogestins like mifepristone inhibit progesterone, which leads to upregulation of
endometrial estrogen receptors, inducing endometrial proliferation and theoretically
reducing vaginal bleeding. Mifepristone 100 mg taken once on the day of insertion
and repeated every 30 days for 3 cycles was associated with a significant decrease
in median duration of intermenstrual bleeding or spotting episodes (6.0 vs 12.5 days;
P 5 .01), as well as number of episodes (2.5 vs 3.0 episodes; P 5 .05). Three months
after treatment, the median duration of intermenstrual bleeding remained lower in those
who were treated with mifepristone (6 vs 15 days; P 5 .008). Satisfaction with the IUD
was also higher in the treatment group, 75% versus 44% (P 5 .004).21
Mifepristone is most commonly used as part of a regimen for medical abortion and
is available in 200-mg tablets. Mifepristone is not currently available as a lower dose,
and the expense of this mediation makes it impractical now.

Selective progesterone receptor modulators

SPRMs like ulipristal acetate also bind with high affinity to the progesterone receptor,
antagonizing the action of progesterone more selectively than mifepristone. Ulipristal
acetate 50 mg daily for 3 days starting 3 weeks after IUD placement and repeated
every 28 days was associated with a decrease in bleeding and spotting days after
the first treatment (equivalent to 3 days less), but that effect was gone at the second
cycle. By the third cycle, ulipristal treatment was associated with an increase in
bleeding and spotting days, equivalent to 6 extra days.22

Summary of Recommendations for Unscheduled Bleeding with the Levonorgestrel

Intrauterine Device
Reassurance should be the first-line recommendation for unscheduled bleeding in
LNG IUD users. For those seeking medical intervention, modest evidence suggests
decreased bleeding with naproxen and mifepristone, though low-dose mifepristone
is not currently commercially available in the United States. One small trial with
tranexamic acid suggests there may be some benefit. Other interventions are not rec-
ommended; mefenamic acid, transdermal estrogen, and ulipristal acetate either have
no effect or increase bleeding.

ETONOGESTREL IMPLANT

The ENG implant (Implanon/Nexplanon [Merck & Co, Whitehouse Station, NJ, USA]) is
associated with an overall decrease in bleeding, with 75% of women reporting fewer
bleeding/spotting days after placement.6 Over 3 months, 22% of ENG implant users
 Therapeutic Options for Unscheduled Bleeding 599

will experience amenorrhea with the rest noting some form of unscheduled bleeding,
including prolonged bleeding (17.7%) and frequent bleeding (6.7%).6,23,24 Up to 23%
of ENG implant users discontinue the device early because of bleeding concerns.5
Another study revealed that 44% of women with unfavorable bleeding patterns
(more bleeding/spotting days) over the first 3 months discontinued prematurely.6
Risk factors for unscheduled bleeding have not been identified, though a favorable
bleeding pattern in the first 3 months (few bleeding/spotting days) seems to predict
a continued favorable pattern during the remainder of use. Even if an unfavorable
bleeding pattern is present in the first 3 months, there is a 50% chance of improvement
over time.6

Treatment of Irregular Bleeding

Studies addressing unscheduled bleeding with the ENG implant have focused on
NSAIDs (ibuprofen and mefenamic acid), MMP inhibitors (doxycycline), antiprogestins
(mifepristone), and estrogen. Table 3 contains a summary of medical interventions
shown to have a benefit in clinical trials for irregular bleeding in ENG implant users.
Limited data exist regarding treatment of unscheduled bleeding in ENG implant
users, and most clinician recommendations are extrapolated from older data in
Norplant (LNG implant) users. Based on data from Norplant, the US selected practice
recommendations (SPR) for contraceptive use (2013) suggests NSAIDs for 5 to
7 days.25 The US SPR for contraceptive use (2013) also recommends low-dose oral
contraceptive pills or estrogen alone for 10 to 20 days if there are no contraindications
to estrogen, though this approach has not been studied with the ENG implant. Use of
cyclic combined oral contraceptives may help to promote scheduled bleeding during
the placebo week and decrease unscheduled bleeding but may lead to more days of
bleeding overall. Evidence from Norplant trials also suggests a benefit from cyclic oral
progestins like medroxyprogesterone acetate 10 mg twice daily for 21 days followed
by a 7-day pill-free interval for up to 3 months, progestin only pills, or tranexamic acid
500 mg twice daily for 5 days.26,27
Nonsteroidal antiinflammatory drugs
A retrospective cohort study used a chart review to see if the ENG implant removal
rate differed for patients who presented for bleeding concerns and were offered reas-
surance alone or reassurance and an additional medical intervention. Thirty-three
percent of those who had an implant placed returned to the office for bleeding
concerns. Of those with bleeding concerns, 70% to 75% ultimately discontinued

Table 3
Efficacy of medical interventions for irregular bleeding/spotting in ENG implant users

Length
Medication Class Medication Dose Frequency of Time
Decreased NSAID Mefenamic acid 500 mg 3 Times daily 5 d
bleeding MMPI Doxycycline 100 mg 2 Times daily 5 d
Antiprogestin Mifepristone 25 mg 2 Times daily 1 d, then
combination Estradiol 20 mcg Daily 4 d
Mifepristone 25 mg 2 Times daily 1 d, then
Doxycycline 100 mg 2 Times daily 5 d
No effect Antiprogestin Mifepristone 25 mg 2 Times daily 1d
on bleeding MMPI and Doxycycline 100 mg 2 Times daily Both for 5 d
estradiol Estradiol 20 mcg Daily

Abbreviation: MMPI, MMP inhibitors.

600 Friedlander & Kaneshiro

the implant early because of dissatisfaction with the bleeding pattern; the discontinu-
ation rate did not differ whether the patients were offered reassurance alone or reas-
surance with ibuprofen.28
Mefenamic acid 500 mg 3 times daily for 5 days was given to ENG implant users
who reported irregular bleeding and was associated with fewer bleeding or spotting
episodes over the subsequent 4 weeks when compared with placebo (10.5 days vs
16.8 days; P<.05). Mefenamic acid users were also more likely to have the bleeding
stop within 1 week (65.2% vs 21.7%; P<.05) and have a bleeding-free interval of
more than 20 days over the next 28-day period (56.5% vs 21.7%; P<.05).29

Matrix metalloproteinase inhibitors

MMPs are expressed in the endometrium and play a role in endometrial tissue remod-
eling. MMP inhibitors like doxycycline inhibit the MMP-mediated matrix degradation
and are thereby thought to help prevent unscheduled bleeding.
In a retrospective cohort study using a chart review to identify ENG implant removal
rates when women with bleeding concerns were offered reassurance alone or an
undisclosed doxycycline regimen, 75.5% discontinued their device early with
reassurance alone, whereas those given reassurance and prescribed doxycycline
had a significantly lower discontinuation rate for bleeding dissatisfaction (45.5%)
(P 5 .005).28
Doxycycline 100 mg twice daily for 5 days was given to women with the ENG
implant experiencing prolonged or frequent bleeding or spotting, with instructions to
start treatment on day 2 of a bleeding episode. Time to bleeding cessation, including
the first day of treatment, was 4.8 days for the doxycycline group compared with
7.5 days with placebo (P 5 .001). However, this benefit did not have an impact on
subsequent bleeding patterns.30 Another trial of doxycycline 100 mg twice daily for
5 days was given in the same patient population but was not associated with a
decrease in time to bleeding cessation (6.4 days for both doxycycline and placebo),
though that trial was inadequately powered (204 participants, 490 required for 80%
power and alpha of 0.05).31

Antiprogestins
Mifepristone 25 mg twice daily for 1 day was given to women with the ENG implant
who had prolonged or frequent bleeding, initiated on the second day of a bleeding
episode. Mifepristone was not significantly associated with a change in time to
bleeding cessation (5.9 days mifepristone, 7.5 days placebo; P 5 .283).30 As
mentioned previously, mifepristone is not commercially available in a 25-mg dose,
and providing the currently available 200-mg dose makes this intervention cost
prohibitive.

Combination therapy: antiprogestins, estrogen, and matrix metalloproteinase

inhibitors
Mifepristone 25 mg twice daily for 1 day followed by estradiol 20 mcg daily for 4 days
was given to women with the ENG implant experiencing prolonged or frequent
bleeding starting on the second day of a bleeding episode. Although mifepristone
alone did not decrease time to bleeding cessation in this study by Weisberg and
colleagues,30 mifepristone with estradiol was associated with a significant decrease
in time to bleeding cessation (4.2 days vs 7.5 days in the placebo group; P<.001).
Despite a benefit in the current bleeding episode, subsequent bleeding episodes
were not delayed or shortened. In a second, larger study with 5 study groups,
Weisberg and colleagues31 noted similar results. Women randomized to receive mife-
pristone 25 mg twice daily for 1 day followed by estradiol 20 mcg daily for 4 days had a
 Therapeutic Options for Unscheduled Bleeding 601

significant decrease in time to bleeding cessation (4 days vs 6.4 days placebo;

P 5 .0008).
Mifepristone 25 mg twice daily for 1 day followed by doxycycline 100 mg twice daily
for 5 days was given to another study group on the second day of a bleeding episode.
This group also had a significant decrease in time to bleeding cessation (4.4 days vs
6.4 days placebo; P 5 .01). Doxycycline 100 mg twice daily with estradiol 20 mcg daily
for 5 days was not associated with a change in time to bleeding cessation (6.4 days for
both treatment and placebo groups).31
None of the combination therapies had an effect on subsequent bleeding patterns
beyond the treatment period.31

Summary of Recommendations for Unscheduled Bleeding with the Etonogestrel

Implant
Reassurance should be the first line in the treatment of irregular bleeding in ENG
implant users. For those seeking medical intervention, modest evidence suggests
use of mefenamic acid, mifepristone with estradiol, mifepristone with doxycycline,
or doxycycline alone. Mifepristone alone was not associated with a decrease
in bleeding. Despite being associated with a decrease in bleeding when used alone,
doxycycline in combination with estradiol was not associated with a significant
change.

SUMMARY

LARC devices, such as IUDs and implants, are the most effective reversible contra-
ceptives available and have few contraindications. Changes in bleeding patterns after
placement are a leading cause of early discontinuation. Fig. 1 is an algorithm on
how to address dissatisfaction with bleeding profiles after device placement. Use of
NSAIDs can be recommended to decrease bleeding with all LARC devices and
tranexamic acid for either IUD. In addition to these recommendations, consider

NSAIDs a
Confirm proper
Copper IUD
placement
Tranexamic acid

If appropriate,
evaluate for NSAIDs
pregnancy,
infection, and
pathology Confirm proper
LNG IUD Tranexamic acid
placement
Reassurance and
education
Mifepristone

NSAIDs a

LNG implant data:

NSAIDs or Doxycycline
ENG Implant estrogen /
combined oral
contraceptives a Mifepristone +
estradiol or
doxycycline

Fig. 1. Management algorithm of bleeding concerns in LARC users. aEndorsed by the US SPR
for contraceptive use (2013).
602 Friedlander & Kaneshiro

additional estrogen, combined oral contraceptives, or progesterone as extrapolated

from Norplant (LNG implant) studies and clinician experience, though no data currently
support or refute its use with currently available LARC devices. More research needs
to be done in this area to try to improve bleeding patterns and user satisfaction with
these highly effective methods.

REFERENCES

1. American College of Obstetricians and Gynecologists. ACOG practice bulletin

No. 121: long-acting reversible contraception: implants and intrauterine devices.
Obstet Gynecol 2011;118:184–96.
2. Moreau C, Cleland K, Trussell J. Contraceptive discontinuation attributed to
method dissatisfaction in the United States. Contraception 2007;76:267–72.
3. Bayer Healthcare Pharmaceuticals Inc. Skyla prescribing information. 2013.
Available at: http://labeling.bayerhealthcare.com/html/products/pi/Skyla_PI.pdf.
Accessed August 17, 2015.
4. Sivin I, Stern J. Health during prolonged use of levonorgestrel 20 micrograms/d and the
copper TCu 380Ag intrauterine contraceptive devices: a multicenter study.
International Committee for Contraception Research (ICCR). Fertil Steril 1994;61:70–7.
5. Casey PM, Long ME, Marnach ML, et al. Bleeding related to etonogestrel subder-
mal implant in a US population. Contraception 2011;83:426–30.
6. Mansour D, Korver T, Marintcheva-Petrova M, et al. The effects of Implanon on
menstrual bleeding patterns. Eur J Contracept Reprod Health Care 2008;
13(Suppl 1):13–28.
7. Makarainen L, Ylikorkala O. Ibuprofen prevents IUCD-induced increases in
menstrual blood loss. Br J Obstet Gynaecol 1986;93:285–8.
8. Suvisaari J, Lahteenmaki P. Detailed analysis of menstrual bleeding patterns after
postmenstrual and postabortal insertion of a copper IUD or a levonorgestrel-
releasing intrauterine system. Contraception 1996;54:201–8.
9. Champion CB, Behlilovic B, Arosemena JM, et al. A three-year evaluation of
TCu 380 Ag and multiload Cu 375 intrauterine devices. Contraception 1988;38:
631–9.
10. Roy S, Shaw ST Jr. Role of prostaglandins in IUD-associated uterine
bleeding–effect of a prostaglandin synthetase inhibitor (ibuprofen). Obstet Gynecol
1981;58:101–6.
11. Toppozada M. Treatment of increased menstrual blood loss in IUD users. Contra-
ception 1987;36:145–57.
12. Wu S, Wang C, Cheng W, et al. Randomized multi-center study of baofuxin for
treatment of bleeding side-effect induced by IUD. Reprod Contracept 2000;11:
152–7.
13. Pizarro E, Mehech G, Hidalgo M, et al. Effect of meclofenamic acid on menstru-
ation in hypermenorrheic women using intrauterine devices. Rev Chil Obstet
Ginecol 1988;53:43–56 [in Spanish].
14. Mercorio F, De Simone R, Di Carlo C, et al. Effectiveness and mechanism of
action of desmopressin in the treatment of copper intrauterine device-related
menorrhagia: a pilot study. Hum Reprod 2003;18:2319–22.
15. Ylikorkala O, Viinikka L. Comparison between antifibrinolytic and antiprostaglan-
din treatment in the reduction of increased menstrual blood loss in women with
intrauterine contraceptive devices. Br J Obstet Gynaecol 1983;90:78–83.
16. Pedron N, Lozano M, Gallegos AJ. The effect of acetylsalicylic acid on menstrual
blood loss in women with IUDs. Contraception 1987;36:295–303.
 Therapeutic Options for Unscheduled Bleeding 603

17. Lin X, Gao ES, Li D, et al. Preventive treatment of intrauterine device-induced

menstrual blood loss with tranexamic acid in Chinese women. Acta Obstet
Gynecol Scand 2007;86:1126–9.
18. Hidalgo M, Bahamondes L, Perrotti M, et al. Bleeding patterns and clinical perfor-
mance of the levonorgestrel-releasing intrauterine system (Mirena) up to two
years. Contraception 2002;65:129–32.
19. Madden T, Proehl S, Allsworth JE, et al. Naproxen or estradiol for bleeding and
spotting with the levonorgestrel intrauterine system: a randomized controlled trial.
Am J Obstet Gynecol 2012;206(129):e1–8.
20. Sordal T, Inki P, Draeby J, et al. Management of initial bleeding or spotting after
levonorgestrel-releasing intrauterine system placement: a randomized controlled
trial. Obstet Gynecol 2013;121:934–41.
21. Lal S, Kriplani A, Kulshrestha V, et al. Efficacy of mifepristone in reducing inter-
menstrual vaginal bleeding in users of the levonorgestrel intrauterine system.
Int J Gynaecol Obstet 2010;109:128–30.
22. Warner P, Guttinger A, Glasier AF, et al. Randomized placebo-controlled trial of
CDB-2914 in new users of a levonorgestrel-releasing intrauterine system shows
only short-lived amelioration of unscheduled bleeding. Hum Reprod 2010;25:
345–53.
23. Darney P, Patel A, Rosen K, et al. Safety and efficacy of a single-rod etonogestrel
implant (Implanon): results from 11 international clinical trials. Fertil Steril 2009;91:
1646–53.
24. Zheng SR, Zheng HM, Qian SZ, et al. A randomized multicenter study comparing
the efficacy and bleeding pattern of a single-rod (Implanon) and a six-capsule
(Norplant) hormonal contraceptive implant. Contraception 1999;60:1–8.
25. Division of Reproductive Health, National Center for Chronic Disease Prevention
and Health Promotion, Centers for Disease Control and Prevention (CDC). U.S.
selected practice recommendations for contraceptive use, 2013: adapted from
the World Health Organization selected practice recommendations for contra-
ceptive use, 2nd edition. MMWR Recomm Rep 2013;62:1–60.
26. Mansour D, Bahamondes L, Critchley H, et al. The management of unacceptable
bleeding patterns in etonogestrel-releasing contraceptive implant users. Contra-
ception 2011;83:202–10.
27. Phupong V, Sophonsritsuk A, Taneepanichskul S. The effect of tranexamic acid
for treatment of irregular uterine bleeding secondary to Norplant use. Contracep-
tion 2006;73:253–6.
28. Casey PM, Long ME, Drozdowicz LB, et al. Management of etonogestrel subder-
mal implant-related bleeding. J Reprod Med 2014;59:306–12.
29. Phaliwong P, Taneepanichskul S. The effect of mefenamic acid on controlling
irregular uterine bleeding second to Implanon use. J Med Assoc Thai 2004;
87(Suppl 3):S64–8.
30. Weisberg E, Hickey M, Palmer D, et al. A pilot study to assess the effect of three
short-term treatments on frequent and/or prolonged bleeding compared to
placebo in women using Implanon. Hum Reprod 2006;21:295–302.
31. Weisberg E, Hickey M, Palmer D, et al. A randomized controlled trial of treatment
options for troublesome uterine bleeding in Implanon users. Hum Reprod 2009;
24:1852–61.