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Update


UPDATE: CONTRACEPTION

Unpredictable bleeding with progestin-only contraceptives can lead to dissatisfaction and discontinuation. The authors scrutinize the reported experience with bleeding changes to help you better counsel your patients.

August 2009 · Vol. 21, No. 08

IN THIS ARTICLE

Dr. Gariepy reports no financial relationships relevant to this article. Dr. Creinin reports that he is a consultant to, and a speaker for, Schering-Plough.

Progestin-only contraception—a diverse group of oral (progestin-only pills, or so-called minipills), injectable (depot medroxyprogesterone acetate), intrauterine (the levonorgestrel intrauterine system), and implantable (etonogestrel implant) methods—may offer advantages over estrogen-containing contraception:

  • the flexibility of distinctive methods of delivery
  • the ability to initiate the method in postpartum breastfeeding women
  • enhanced safety in women who should not be exposed to exogenous estrogens.

Unpredictable bleeding is a major disadvantage of progestin-only contraception, however, and can cause women to discontinue these methods—and discontinuation without an effective backup method creates a high risk of unplanned pregnancy. The significant variability in bleeding patterns among progestin-only contraceptive methods hinders our ability to counsel patients about them.

Furthermore, the lack of uniform definitions of bleeding patterns with hormonal contraception, including progestin-only methods, makes it difficult to counsel women accurately and compare bleeding patterns among methods.

Accurate prediction of the bleeding patterns associated with progestin-only contraception could lower the discontinuation rate. For example, studies have shown that pretreatment counseling about expected side effects increases approximately fourfold the acceptability and continuation of depot medroxyprogesterone acetate.1,2

In this Update, we review the data on bleeding patterns associated with progestin-only contraceptives, including the likelihood of 1) amenorrhea and 2) discontinuation due to changes in the bleeding pattern.

We also discuss what has been learned about the treatment of changes in bleeding patterns induced by progestin-only contraception.

Our goal? To summarize the findings in a comprehensive way that makes it easier for you to discuss expected bleeding patterns with your patients—so that women can choose the method of contraception that is the best fit for them.

Describing bleeding patterns is a challenging task

One of the difficulties of interpreting clinical data on bleeding patterns—with any type of contraception—is the lack of a universally accepted standard for collecting and reporting these data. The first suggestions for standardization were made in 1976, when Rodriguez and colleagues proposed using 90-day reference periods for analysis, as a way to minimize variability among individual menstrual cycles.3

Subsequently, the World Health Organization’s (WHO’s) Special Programme of Research, Development and Research Training in Human Reproduction developed recommendations for data collection, terminology, presentation, and data analysis when reporting vaginal bleeding during clinical trials of hormonal contraception. These recommendations became known as the WHO Belsey criteria (TABLE 1). They remain the standard.4

Under the WHO Belsey system:

  • vaginal blood loss for which a woman uses sanitary protection is classified as bleeding
  • vaginal blood loss that does not result in the use of sanitary protection is considered spotting.

This system also specifies indices for evaluating the bleeding pattern for each woman and reference period, including the number of bleeding-spotting days, number of bleeding-spotting episodes, lengths of bleeding-spotting episodes, and bleeding-spotting-free intervals. A bleeding-spotting episode is defined as one or more consecutive days during which blood loss (bleeding or spotting) has been recorded, each episode being bounded by bleeding-spotting-free days. The WHO Belsey criteria also identified subgroups that have “clinically important bleeding patterns” (TABLE 1).

But not all researchers use the WHO Belsey criteria. Many trials use, and report, their own system of analysis. Some researchers have chosen reference periods of other durations and study periods that range from 1 to 5 years. Some studies report bleeding patterns by number of days, and others report the percentage of women experiencing a given bleeding pattern during a reference period. The lack of uniformity results in data that are difficult to compare from one study to the next—and to explain to our patients.

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It’s unclear whether any of our research definitions of clinically significant bleeding have ever been validated as clinically important to our patients. Multiple studies do show that changes in menstrual bleeding patterns are a significant cause of dissatisfaction with any given contraceptive method, but we don’t know if the number of days of bleeding-spotting or the predictability of this bleeding-spotting is the critical piece of information we should be relating to our patients.

In other words, do our beliefs about clinically important bleeding patterns reflect women’s beliefs?

TABLE 1

The WHO Belsey system of bleeding patterns

Pattern

Definition

Amenorrhea

No bleeding

Prolonged bleeding

1 or more bleeding-spotting episodes lasting longer than 14 days

Frequent bleeding

More than 5 bleeding-spotting episodes

Infrequent bleeding

1 or 2 bleeding-spotting episodes

Irregular bleeding

3 to 5 episodes with more than 3 bleeding-free intervals of 14 days or longer

Normal bleeding

None of the above are present

This system establishes criteria for defining clinically important bleeding patterns during a 90-day reference period. Adapted from: Belsey EM et al.4

Implantable contraception

The etonogestrel (ENG) implant (Implanon) is the only implantable contraceptive available in the United States. This single-rod contraceptive can be used for as long as 3 years.

Contraceptive implants, including the levonorgestrel implants once sold in the United States and still available in some parts of the world, are highly effective. The Implanon prescribing information reports a first-year failure rate of 0.38 pregnancies for every 100 woman-years of use; Hatcher and co-workers reported a failure rate of 0.5 The difference is based on how the FDA defines pregnancy in contraceptive trials. In fact, the only pregnancies reported with the ENG implant happened after it was removed. Importantly, the studies evaluated by the FDA included only women not using any medications known to induce liver metabolism (the cytochrome P450 pathway) and who were between 80% and 130% of ideal body weight. The efficacy of the ENG implant for women who are taking medications that induce liver metabolism or who are greater than 130% of their ideal body weight is unknown.

The efficacy of the ENG implant is likely derived from suppression of ovulation and increased cervical mucus viscosity. Associated changes in the endometrium that occur with this low dosage of progestin are likely the primary cause of irregular and unpredictable bleeding.

Several studies have sought to describe the bleeding patterns experienced with the ENG implant.6-8 During the first 3 months, approximately 50% of all women using the ENG implant reported bleeding-spotting (TABLE 2) for 30 days, on average (TABLE 3). The number of days decreases to approximately 20 bleeding-spotting days for each 90-day reference period at 6 to 24 months, with wide variability. For example: From 3 to 6 months, women reported 22 days of bleeding-spotting (standard deviation, 20 days); from months 21 to 24, 20 days of bleeding-spotting (standard deviation, 14 days).7

After using the ENG implant for 2 years, therefore, most women can expect the number of bleeding-spotting days for every 90-day reference period to range between 6 and 34 days. These days of bleeding-spotting are often noncontinuous, however. On average, women reported three separate bleeding-spotting episodes for every 90-day reference period.7

Although individual bleeding patterns are unpredictable, women who had no bleeding, or infrequent bleeding, at the beginning of use of the ENG implant had only a “small chance” of bleeding frequently.6 The most common bleeding pattern observed throughout the study was infrequent bleeding, defined as fewer than three episodes of bleeding in a 90-day reference period (excluding amenorrhea).7

Amenorrhea may not persist. The amenorrhea rate at 6 months of use and beyond ranges from 10% to 20% (TABLE 4). Importantly, women who are amenorrheic in one 90-day reference period are not necessarily the ones who are amenorrheic in another reference period. So, unlike what is more commonly seen with other progestin-only methods, such as injectables, amenorrhea is not sustained for most women.

This unpredictable pattern affects continuation of the ENG implant (TABLE 5). Irregular bleeding is the most common reason women cite for discontinuation, accounting for 30% to 60% of all women who discontinue early.7,9

Overall, approximately 4% of ENG users discontinue the method at 1 year. Ten percent to 20% discontinue each year thereafter because of intolerance to bleeding changes.6-9

There are, however, differences in discontinuation rates across cultures. In an integrated analysis of 13 different trials that evaluated patterns of vaginal bleeding with the ENG implant where the rate of menstrual changes was similar, women from Europe and Canada were much more likely (23%) to discontinue the implant because of those changes than women from Southeast Asia and Chile were (2%).6 This finding may reflect differences in cultural beliefs or disparate access to other contraceptive options.10

TABLE 2

What percentage of women taking progestin-only contraception report bleeding-spotting?

 

Months

Study

3

6

9

12

18

24

DMPA

Sangi-Haghpeykar (1996)33

46%

43%

40%

Cromer (1998)34

24%

10%

 

ENG implant

Croxatto (2000)9

40–50%

 

LNG-IUS

Datey (1995)32

18%

6%

3%

1%

 

4%

Hidalgo (2002)20

 

25%

 

8%

11%

Progestin-only pill

Sheth (1982)35

21–55%*

 

6–42%*

 

* Percentage reporting prolonged, frequent, or irregular bleeding.

Key: DMPA, depot medroxyprogesterone acetate; ENG implant, etonogestrel implant; LNG-IUS, levonorgestrel intrauterine system.


TABLE 3

How many days of bleeding-spotting do women have
when they use progestin-only contraception?

 

Months

Study

0–3

4–6

7–9

10–12

13–15

16–18

19–21

22–24

36

DMPA

Belsey (1988)11

16*

9

4

3

 

Hubacher (2009)31

21

18

14

10

 

ENG implant

Affandi (1998)6

26

19

16

16

17

18

18

18

 

Zheng (1999)8

34

22

19–22

Funk (2005)7

31

22

19

19

18

19

17

20

 

LNG-IUS

Datey (1995)32

 

Total days of bleeding

9

7

6

5

 

5

5

Total days of spotting

10

5

5

4

 

4

4

Progestin-only pill

Belsey (1988)11

15–18

 

*All values in the table represent an average number of days in a 90-day reference period.

Key: DMPA, depot medroxyprogesterone acetate; ENG implant, etonogestrel implant; LNG-IUS, levonorgestrel intrauterine system.

TABLE 4

What percentage of women taking progestin-only contraception report amenorrhea?

 

Months

Study

3

6

9

12

24

DMPA

Belsey (1988)11

8%

22%

39%

45%

 

Sangi-Haghpeykar (1996)33

46%

53%

59%

 

Cromer (1998)34

34%

60%

 

Polaneczky (1998)14

23%

40%

65%

40%

 

Canto (2001)1

35%

 

70%

 

Jain (2004)13 (DMPA-SC)

26%

38%

 

55%

 

Hubacher (2009)31

12%

25%

37%

46%

 

ENG implant

Affandi (1998)6

2%

19%

25%

23%

21%

Zheng (1999)8

2%

19%

10%

15%

 

Croxatto (2000)9

 

12-20%

Funk (2005)7

2%

14-20%

LNG-IUS

Andersson (1994)21

 

17%

 

Hidalgo (2002)20

 

44%

 

50%

50%

Progestin-only pill

Belsey (1988)11

0%

0%

0%

0%

 

Sheth (1992)35

3-8%

 

0-2%

 

Kovacs (1996)24

 

5-10%

 

Key: DMPA, depot medroxyprogesterone acetate; ENG implant, etonogestrel implant; LNG-IUS, levonorgestrel intrauterine system.

TABLE 5

What percentage discontinue progestin-only contraception
because of a change in bleeding pattern?

 

Months

Study

3

6

9

12

24

36

DMPA

Potter (1997)36

 

43%

 

Sangi-Haghpeykar (1996)33

34.1%

58%*

78%*

 

Davidson (1997)37

31%

49%*

 

58%

 

ENG implant

Croxatto (2000)9

 

19%

Zheng (1999)8

 

4%

6.1%*

8.4%*

Affandi (1998)6

 

23%

Funk (2005)7

 

13%

 

LNG-IUS

Datey (1995)32

 

13.8%

 

Luukkainen (1987)38

 

7.5%

 

Andersson (1994)21

 

5.8%*

8.3%*

9.6%*

Progestin-only pill

Belsey (1988)39

 

10%

 

Sheth (1982)35

 

25%

34.5%*

 

Graham (1992)25

18%

25%

35%*

 

*Percentages are cumulative across the months studied.

Key: DMPA, depot medroxyprogesterone acetate; ENG implant, etonogestrel implant; LNG-IUS, levonorgestrel intrauterine system.

PERSPECTIVE AND GUIDANCE FOR YOUR PRACTICE

The pattern of bleeding seen with the ENG implant is like the activity of the heart in atrial fibrillation: irregularly irregular. Still, most (80%) women continue to use it beyond 1 year. In fact, the discontinuation rate for the ENG implant is less than that of depot medroxyprogesterone acetate (DMPA) and progestin-only pills.

Most ENG implant users report no difficulty tolerating the associated unpredictable bleeding; it’s possible that they had unpredictable bleeding at baseline, or were drawn to the improvement in their dysmenorrhea.6

Importantly, unpredictable bleeding does not affect efficacy; the ENG implant remains one of the most effective long-acting reversible contraceptives. For women who can tolerate unpredictable bleeding, the ENG implant is a highly effective contraceptive option.

Injectable contraception

Approved by the FDA in 1992, DMPA (Depo-Provera) has good efficacy and long-acting protection. Disadvantages include unpredictable bleeding, weight gain, acne, depression, hair loss, and the controversial issue of decreased bone loss with prolonged use.

What are the expected changes in bleeding patterns with DMPA? Women often have unpredictable patterns, with infrequent but prolonged bleeding-spotting episodes.11 The overall incidence of irregular bleeding can be as high as 70% in the first year of use.12 Irregular bleeding decreases with continued use, to as low as 10% after the first year (TABLE 2).

Although the number of bleeding-spotting days decreases over time, women have reported as many as 10 days of irregular bleeding-spotting between 9 and 12 months of use (TABLE 3). The rates of irregular bleeding and amenorrhea are similar for the subcutaneous formulation of DMPA.13

Continued...
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