This chapter should be cited as follows: Under review - Update due 2018
Meckstroth, K, Darney, P, Glob. libr. women's med.,
(ISSN: 1756-2228) 2008; DOI 10.3843/GLOWM.10399

Contraception

Implantable Contraception

Karen R. Meckstroth, MD, MPH
Clinical Instructor, Department of Obstetrics, Gynecology, and Reproductive Science, San Francisco General Hospital, San Francisco, California
Philip D. Darney, MD, MSc
Professor and Chair, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, California

INTRODUCTION

Thanks to innovation in hormonal contraception since the introduction of oral contraceptive pills, women today may choose from several delivery systems that offer sustained-release of hormones. Subdermal contraceptive implants provide constant delivery of a very low dose of progestin that provides extremely effective contraception from 1 to 7 years. The six-capsule levonorgestrel system (Norplant) was the first of these, and it is estimated that about 9 million women worldwide have used or are using this method.1 The vast majority of evidence on implants arises from studies of levonorgestrel-releasing implants. Newer implants contain levonorgestrel and other progestins and permit similar drug release from only one or two implants rather than six, leading to faster and easier placement and removal. Implanon, a single-rod implant containing etonogestrel, is approved for 3 years of use in the European Union, Canada, and Indonesia and is expected to be approved for use in the United States in 2003. Years of research on Norplant and other systems have demonstrated the efficacy, safety, and acceptability of implants.

ACCEPTANCE AND PERCEPTIONS

Consideration of implants as a contraceptive option depends on clinician counseling as well as positive perceptions among the general public. Studies in multiple countries of women using implants have indicated that perceptions of implants among users are favorable and that acceptance is high.2,3,4,5,6 Women who use implants have identified ease of use (79%) and high effectiveness (30%) as the most desirable features.4,5,7,8,9 The majority of users (54%) reported that difficulty or dissatisfaction with other methods of contraception was a primary reason for choosing implants, with most women reporting previous use of three or more methods of birth control. These women also considered convenience and ease of use highly important in their decision to use implants, even though use of the device required a minor surgical procedure for insertion and removal. When Norplant users in San Francisco clinical trials were asked if they would recommend Norplant to their friends, 91% said they would, and 71% said they themselves would use Norplant again.9 Although many women discontinue implants because they want to become pregnant, side effects are the primary reasons for early removal in most studies. Irregular or prolonged uterine bleeding is by far the most common reason sited for early removal of implants.10,11,12 Other reasons include headache, mood swings, weight gain, depression or nervousness, acne, abdominal or general discomfort, and arm pain.13,14,15,16,17

Many teenagers are ideal candidates for implant contraception because they desire a method that is discreet, effective, inexpensive, and long-lasting, preserves fertility, and does not require much of the user. Unfortunately, only about 3% of adolescents using contraception choose implants.18 Several studies have evaluated adolescents’ use of levonorgestrel implants.19,20,21,22,23,24,25 In general, acceptance and satisfaction rates are high, continuation rates are equivalent to those of adult users, and pregnancy rates are very low. As in adult populations, thorough counseling and good follow-up are essential elements of successful use.

DESCRIPTION OF IMPLANTS

Norplant

The Norplant system consists of six capsules containing a total of 216 mg levonorgestrel. Each is 34 mm long and 2.4 mm in diameter. The capsules are made of flexible, medical-grade Silastic (polydimethylsiloxane) tubing that is sealed closed. Implants analyzed after 5 years of use still contain about 50% of the original, unaltered levonorgestrel.26 The six capsules are inserted in a fan configuration in the medial upper arm.

Jadelle (Norplant II)

A two-rod levonorgestrel implant has been under study for over 2 decades and is currently available in several countries in Europe. A similar implant is available in the People’s Republic of China. The European implant initially was called Norplant II and is currently distributed under the trade name Jadelle (Schering, Berlin). This system is approved by the U.S. Food and Drug Administration (FDA), but there are no plans at this time to market it in the United States. The two-rod system contains 150 mg of levonorgestrel in two longer (4-cm), covered rods.27 Because the daily release rate is identical to the six-capsule system, the maximal theoretical life is about 40% shorter.7,28 Given that Norplant is clearly effective beyond its FDA-approved 5-year duration, it is not surprising that in comparative clinical trials, the 5-year pregnancy rates and side effects of Jadelle were equal to the six-capsule Norplant.29,30 In fact, the Population Council has recently filed for approval of Jadelle for 5 years of use and Norplant for 7 years of use.31 The cumulative 5-year pregnancy rate per 100 woman-years with Jadelle is between 0.8 and 1.0,32,33 which, like Norplant, is less than 0.2 per year.

Implanon

Implanon (Organon, Oss, Netherlands) is a single subdermal implant rod that contains the progestin etonogestrel (3-ketodesogestrel), a desogestrel metabolite that has less androgenic and more progestational activity than levonorgestrel.34 The carrier polymer, ethylene vinyl acetate, provides a more stable release rate than the Silastic capsules of Norplant, and variability of serum levels is less with Implanon.35 Many studies have examined the safety, efficacy, and acceptability of Implanon, and several European and Asian countries have made it available to women. Implanon is expected to be available in the United States in 2003. The single implant comes in a disposable sterile inserter that functions as the trocar for insertion and guides correct subdermal placement.36 Insertion and removal require about 1 and 2 1/2 minutes.37 Unlike Norplant and Jadelle, Implanon was designed with the specific aim of inhibiting ovulation during the entire treatment period. Because the first ovulations and luteinizations occur in the second part of the 3rd year,38 the duration of use has been restricted to 3 years, even though excellent efficacy has been demonstrated for at least 4 years.39 With no pregnancies in the first 70,000 cycles studied, Implanon may have the highest efficacy of any contraceptive method developed so far.40

Other Implants

The Population Council has developed a single-implant system using Nestorone, or ST-1435. Nestorone is a potent progestin that effectively inhibits ovulation,41 does not bind to sex hormone–binding globulin (SHBG) and has no estrogenic or androgenic activity.42 Nestorone is biologically inactive when given orally owing to rapid first-pass hepatic metabolism and, therefore, is not active in the children of breastfeeding women.43,44 Studies have investigated various sizes of the implant and have found that a single 4-cm implant provides 2 years of contraception,42 but that the higher dose obtained from two 3-cm implants can inhibit ovulation beyond 2 years. A higher-dose single capsule implant is now in a three-center clinical trial.31 A single nesterone implant is registered in Brazil under the name Elcometrine for 6 months of use for the treatment of endometriosis.

Uniplant is a single capsule containing nomegestrol acetate, a 19-nor-progesterone derivative that has been available in Europe in the oral form for several years. In an ongoing multicenter trial of 1800 women in nine countries, the 1-year pregnancy rate was 1.1%, slightly higher than other implants.45,46,47 There are no plans to market Uniplant at this time.48 Several biodegradable implants have also been investigated, but none is close to registration.

PROGESTINS AND RELEASE RATES

Sustained-release systems rely on simple diffusion of steroid hormones through semipermeable plastics. The synthetic progestin passes from the plastic into the surrounding tissues and enters the circulatory system through absorption by the local capillary network. Plasma levels of levonorgestrel from Norplant, for example, are stable at 0.4 to 0.5 ng/mL within 24 hours after insertion.26 The release rate of the progestin depends on the surface area and diffusion capacity of the tubing and, in some systems, the material in which the progestin is suspended. Levonorgestrel was selected for use in Norplant because of its high progestagenic potency and low pregnancy rates in early trials. New implant systems use other progestins such as etonogestrel in Implanon. Etonogestrel is the active metabolite of desogestrel, a low-androgenic gonane. Desogestrel has been shown to more completely suppress follicular growth than levonorgestrel in comparisons of combined oral contraceptive pills (OCPs) containing the two closely related progestins.49

During the first 6 to 12 months of use, Norplant and Jadelle release a total of about 80 mg of levonorgestrel every 24 hours, giving a plasma concentration of 0.35 ng/mL. After the first year, the release rate gradually declines to a relatively constant rate of 30 to 35 mg/day. At 5 years, the overall release rate is 25 mg/day, with corresponding levonorgestrel levels of 0.25 to 0.35 ng/mL. For comparison, progestin-only OCPs also deliver about 80 mg of levonorgestrel per day; combined oral contraceptives with levonorgestrel as the active progestin deliver 50 to 125 mg. Peak serum levels after ingestion of 75 mg of levonorgestrel reach 1.5 to 2.0 ng/mL; after ingestion of 150 mg of levonorgestrel, serum peaks reach 2.7 to 4.2 ng/mL. These serum peaks are reached from 30 minutes to 2 hours after ingestion and are followed by a rapid decline, with an average half-life of 10 to 12 hours.50 This is in contrast to the stable, low serum concentrations of progestin achieved with the sustained-release systems. Serum levels of etonogestrel in women using Implanon follow a similar concentration-time curve as with Norplant.51

MECHANISM OF ACTION

Implants prevent pregnancy by several mechanisms. Like other progestin-only methods, implants cause thickening of the cervical mucus. Even a very low level of sustained progestin leads to cervical mucus that is scanty, viscous, and impenetrable to sperm.52,53 Mucus changes take place rapidly after insertion of progestin implants.54 The progestin also acts at the hypothalamus and pituitary to suppress the release of follicle-stimulating hormone and luteinizing hormone (LH). The LH peak is dampened so that ovulation is inhibited with levonorgestrel implants (Fig. 1). The LH level is more completely suppressed by Implanon, resulting in no LH surges or ovulations for the first 3 years of use.55 In addition, prolonged use of progestin alters the maturation of the endometrium, resulting in a hypotrophic uterine lining, which is unsuitable for implantation.56 This effect is more uniform in Implanon users compared with that in Norplant users, a small percentage of whom form secretory endometrium after the1st year.56,57 Whereas endometrial changes are important to understand in regard to irregular bleeding, the alteration is relatively unimportant for implant efficacy. Implanon users do not ovulate, and Norplant users rarely experience elevations in human chorionic gonadotropin levels, suggesting that fertilization is an unusual event even when ovulation is common.58

Fig. 1. Mean luteinizing hormone (LH) levels during menstrual cycles of Norplant users and controls.(Alvarez F, Brache V, Tejada AS, et al: Abnormal endocrine profile among women with confirmed or presumed ovulation during long-term Norplant use. Contraception 33:111, 1986)

Follicular activity without ovulation is demonstrated in both Implanon and Norplant users by near-normal estradiol levels in the absence of elevated progesterone (Fig. 2).55 Because ovarian estradiol activity is variable, women using implants may develop palpable, but rarely symptomatic, physiologic ovarian cysts.55 These cysts usually resolve spontaneously within a few weeks and are rarely an indication for surgery or removal of the implants.

Fig. 2. Mean serum estradiol concentrations for Implanon and Norplant users. T-bars represent the percentile range of P5 to P95; boxes represent the percentile range of P25 to P75.(Huber J, Wenzl R: Pharmacokinetics of Implanon: An integrated analysis. Contraception 58[Suppl 6]:85S, 1998)

METABOLIC EFFECTS

Studies assessing the metabolic effects of progestin implants have shown no significant alterations in liver function,59,60,61,62,63 thyroid function,64,65,66,67 adrenal function,64,66,68,69 coagulation,62,63,70,71 levels of immunoglobulins,72,73 or blood chemistries.61,72

Carbohydrate Metabolism

Progestin implant contraceptives may induce a mild increase in insulin resistance in healthy users. Most studies have found no changes in carbohydrate metabolism outside of the normal range in women who use implants,59,74,75 although several studies have noted changes that were statistically significant, but very small in magnitude. Croxatto and coworkers found that mean fasting serum glucose levels were slightly, but significantly, elevated in levonorgestrel implant users compared with intrauterine device (IUD) users (controls), but no values were outside of the normal range.72 One randomized trial of etonogestrel and levonorgestrel implant users found a minimal but statistically significant increase in fasting glycosylated hemoglobin A1c levels at 24 months in the Implanon group.76 Few studies have examined the impact of progestin implants on women with diabetes or impaired glucose tolerance. Data from women using other forms of progestin-only contraception suggest the methods may increase the risk of diabetes in some populations. A retrospective study of breastfeeding Latina women with recent gestational diabetes found that women using progestin-only OCPs had an increased risk of developing type 2 diabetes (adjusted risk ratio [RR], 2.87).77 However, implants lead to lower serum levels of progestin and may not have a similar impact. One study that included implant users found that, whereas fasting glucose increased in diabetic women using depo-medroxyprogesterone acetate (DMPA) and combined OCPs, glucose was not altered in Norplant users.78 Overall, the minimal changes in carbohydrate metabolism that occur with progestin implants are unlikely to be clinically significant in healthy users. It is not clear whether implants pose a negligible or a slightly increased risk to women with or at risk for diabetes.

Lipoprotein Levels

Concern over possible deleterious alterations in lipoproteins caused by continuous progestin have prompted many studies of lipoprotein levels in implant users. Studies tend to agree that implant use leads to a decrease in total cholesterol and triglycerides, with little change in the high-density lipoprotein-to-cholesterol ratio. Continuous low-dose levonorgestrel or etonogestrel may result in minor decreases in low-density lipoproteins.72,79,80,81,82,83,84,85,86,87,88,89,90 There is general agreement that long-term use of progestin implants or other sustained-release systems is unlikely to affect the risk of atherogenesis. Although the majority of lipid studies have examined users of levonorgestrel implants, Implanon appears to lead to very similar lipid changes.79

Sex Hormone-Binding Globulin

Most progestins given without estrogen decrease SHBG, leading to increased levels of free androgens. Levonorgestrel is an androgenic steroid that decreases levels of SHBG. The net effect is usually insignificant, although some women may experience side effects of increased androgen, such as acne and weight gain. These effects may be less in users of implants containing minimally androgenic progestins, such as etonogrestrel, or nonandrogenic progestins such as Nestorone. A small comparative trial found that Norplant suppressed SHBG concentration about 26% more than Implanon (p = .001). Concentrations of SHBG recovered at an average rate of 6% per year in both groups.38

BONE DENSITY

It is plausible that prolonged exposure to high doses of progestins could lead to decreased bone mineral density (BMD) by suppressing follicular estradiol production. After a 1991 study linked DMPA to reduced BMD,91 researchers began to examine implant contraceptives for this adverse effect. Studies have resulted in varied results owing in part to different research designs, techniques for measuring BMD, and age of participants.92 Evidence suggests that bone density is stable or increases with short-term use of levonorgestrel implants93,94,95 and Implanon.96 If there is a differential effect on BMD between levonorgestrel implants and DMPA, it is probably attributable to less suppression of the pituitary gland by implants, permitting more follicular activity in the ovary and more estrogen production.92 All changes in BMD appear to be transient and reversible with discontinuation of the steroid contraceptive.97 Although Implanon causes a higher degree of pituitary suppression than does Norplant, ovarian hormonal activity is still present and estradiol levels are similar in women using the two implant systems.55

EFFICACY

Implants are extremely effective contraceptive options. No pregnancies occurred in studies undertaken during the development of Implanon. These studies evaluated over 4103 women-years of Implanon use.55 Norplant and Jadelle have nearly identical efficacy rates and are more effective than sterilization in the1st year98 and comparable with sterilization at 5 to 7 years.99,100,101,102 Like sterilization, implants require no maintenance by the user, so typical and theoretical effectiveness are equivalent. Table 1 summarizes efficacy rates for different contraceptive options.

Implant efficacy is related to serum progestin concentration.103 Several factors affect progestin serum levels, including duration of use, body weight, and concentration of SHBG. Women with higher body weight (>70 kg) have lower progestin levels than women with lower weight,51,104 and lower efficacy has been noted in heavier women using Norplant and Jadelle.27,101,105,106 Even in heavy women, though, annual pregnancy rates are less than 1%.106 Serum progestin levels are also lower in heavier women using Implanon, but as studies have had no failures, differences in efficacy were not identified.51 The decrease in levonorgestrel serum concentration is approximately 0.0033 Μg/L for each kilogram of weight. Some evidence suggests that progestin levels may not correlate directly with efficacy, and that the serum progestin-to-SHBG ratio may be a better predictor of efficacy.107 A decrease in SHBG will lead to increased free levonorgestrel and therefore faster clearance of the drug.108 Nestorone42 and nomegestrol109 do not stimulate changes in SHBG levels and would not have this effect.

 

TABLE 1. Percentage of U.S. Women Experiencing Contraceptive Failure, by Duration of Use and Method, According to Correction for Abortion Underreporting, 1995 National Survey of Family Growth


  

Corrected

Duration and Method

Uncorrected

Unstandardized

Standardized

First 6 Mo of Use

Total

 5.0

 7.1

 7.0

Implant

 0.0

 0.1

 0.1

Injectable

 1.2

 1.1

 0.9

Pill

 2.6

 3.9

 3.8

Diaphragm/cervical cap

 4.9

 6.5

 7.8

Male condom

 5.1

 8.2

 8.1

Spermicides

 7.0

14.6

15.7

Withdrawal

11.0

13.9

14.1

Periodic abstinence

12.2

13.9

16.7

First 12 Mo of Use

Total

9.1

12.1

11.8

Implant

 1.7

 1.8

 1.3

Injectable

 2.6

 3.1

 2.5

Pill

 6.6

 7.6

 7.3

Diaphragm/cervical cap

 8.4

12.1

14.4

Male condom

 9.0

13.9

13.8

Spermicides

15.1

25.7

27.0

Withdrawal

18.2

23.6

24.1

Periodic abstinence

18.9

20.5

24.3


Trussel J, Vaughan B: Contraceptive failure, method-related discontinuation and resumption of use: Results from the 1995 National Survey of Family Growth. Fam Plann Perspect 31, 1999

 

ECTOPIC PREGNANCY

The risk of developing an ectopic pregnancy in implant users is dramatically decreased compared with the risk in noncontraceptors. Levonorgestrel implant users experience an ectopic rate of 0.28 to 1.3 per 1000 women-years101,104,106 compared with 2.6 per 1000 woman-years in women not using contraception.110 In the case of the rare woman who becomes pregnant while using implants, the chance that that pregnancy is ectopic is higher because the method prevents intrauterine implantation more effectively than extrauterine implantation. Progestin implants such as Implanon that prevent ovulation protect against ectopic pregnancy even more effectively.

FUTURE FERTILITY

The use of implants has no long-term effects on fertility. After removal of Implanon, serum concentrations of etonogestrel are undetectable within 1 week.51 Forty-eight hours after removal of levonorgestrel implants, plasma levonorgestrel levels are almost undetectable. In only two of many trials of implants have subsequent fertility rates been below those considered “normal,” and both followed women in countries in which underreporting of selective abortion was likely.111,112 After Norplant use, there have been no effects on rates of ectopic pregnancy, stillbirth, spontaneous abortion, or congenital malformations.101

ADVANTAGES OF IMPLANTS

Advantages and disadvantages of implants are summarized in Table 2. Implants have several major advantages as a contraceptive option. Among the most important advantages are their high effectiveness and ease of use. Because implants require little of the user after insertion, their use-effectiveness is nearly identical to their theoretical effectiveness. Implants require only an initial insertion procedure, then provide continuous and highly effective, non–coitus-related protection for several years. The contraceptive effect of implants is easily and quickly reversible with removal of the implants. Progestin implants have not been associated with long-term health risks and may safely be used by women with contraindications to estrogen-containing steroid contraceptives. As described earlier, implants use a very low serum level of progestin and cause minimal metabolic effects. These low serum levels are also extremely stable compared with hormonal methods that require more frequent dosing or replacement. Although implants do not protect against sexually transmitted infections (STIs), the constant serum progestin level leads to thickened cervical mucus, which may protect against upper genital tract infection. Postmarketing surveillance found that Norplant users had a relative risk of pelvic inflammatory disease (PID) of 0.25 compared with IUD users, despite a very low PID risk in the IUD users.111,113 Although the initial cost of implants is high, when the effectiveness and lack of continuing costs are considered, the cost for implant contraception is on a par with vasectomy and the copper-T IUD and more cost-effective than oral contraceptives, barrier methods, or ovulation-timing.114 One study found Implanon to be extremely cos-effective, with a “payback” period of 146 days, less than half that for Norplant (349 days) and the levonorgestrel IUD Mirena (368 days).115 For women who receive implants through subsidized programs or insurance, low cost for a long duration of action is valued.2

 

TABLE 2. Advantages and Disadvantages of Implant Contraceptives

  Advantages
  High efficacy
  Long-term action
  Convenience of use, minimal maintenance
  Dissociation of use from intercourse
  Rapid return to fertility after discontinuation
  Rapid onset of action
  Protection against ectopic pregnancy
  Minimal metabolic effect
  Absence of estrogen
  Maintained endogenous estrogen levels/maintained bone density
  Low relative cost
  Possible protection against upper genital tract infection
  Disadvantages
  Menstrual irregularities
  Surgical procedure required for initiation and removal
  No protection against sexually transmitted infections
  Side effects for some women
  Effects That May Be Positive or Negative
  Implants are visible or palpable under the skin
  Amenorrhea
  Weight change (gain or loss)

 

DISADVANTAGES OF IMPLANTS

Provider-Controlled

The use of implant contraceptives requires minor surgical procedures for both insertion and removal. Women therefore cannot initiate or discontinue the method without consulting a trained clinician. Systems with one (Implanon and Uniplant) or two (Jadelle) implants rather than the six of the original Norplant are faster and easier to insert and remove.

No Protection Against Sexually Transmitted Infections

Unlike barrier contraceptives, hormonal methods, including implants, cannot offer protection against STIs. As noted previously, their effects on cervical mucus likely afford a degree of protection from PID. Women using implants who are at risk for STIs should be advised of their continuing need for condoms to prevent infection. The high efficacy of implants could lead to the patients abandoning condoms unless they are made aware that STIs remain a risk. Some studies have found that high-risk women who choose effective methods of birth control such as implants use condoms less frequently than women who choose condoms as their primary method.116 Such women have not shown an increase in STIs.117 Unfortunately, women who use condoms as their primary method have a low rate of perfect use and are exposed to both STIs and pregnancy. Although the mechanism of protection is unclear, vaginitis was reported to be half as common in Norplant users as in women using a copper IUD.118

Implants May Be Palpable or Visible

Slender women using implants may find the capsules are visible under the skin. In most cases, the implants are palpable but not visible. Although some women and their partners may find it comforting to be able to visualize their effective contraception, most do not view this as an advantage. Women with dark skin may experience some skin discoloration over the implants, which gradually disappears after removal. Both of these effects are less severe in women using systems with only one or two, rather than six, implants.

MENSTRUAL IRREGULARITIES

All progestin-only contraceptives cause alterations in the normal pattern of menstrual bleeding, a side effect that leads to discontinuation for many women. About 80%t of women using implants report alterations in their menstrual pattern at some time while using the device. Most commonly, women report episodes of prolonged spotting in an irregular pattern, although oligomenorrhea and amenorrhea also occur. These changes may occur at any time but are most common during the 1st year of use and then decline steadily over the following years. On average, the total number of bleeding days increases during the 1st year of use, but the total blood loss decreases, resulting in an overall increase in mean hemoglobin levels. After the 1st year of levonorgestrel implant use, in addition to a further decrease in the quantity of blood lost, the number of bleeding days also declines from an average of 90 spotting and bleeding days during the 1st year to 70 during the 5th year.101,119,120 An analysis of 13 comparative trials of Implanon and Norplant found that Implanon users experienced more variable bleeding patterns but an overall decrease in the number of bleeding days and episodes compared with Norplant users. Implanon users had a higher incidence of amenorrhea and a slightly higher incidence of infrequent bleeding, frequent bleeding, and prolonged bleeding121 (Table 3). In cases in which women report sudden amenorrhea after a period of cyclic menses, a pregnancy test should be performed to reassure both the physician and the woman that pregnancy has not occurred.

 

TABLE 3. Parameters of Bleeding Patterns in Completers and Discontinuers During the First 2 years of Use*


 

Implanon

Norplant

Parameter

Completers (n = 169, nRP = 789)

Discontinuers (n = 46, nRP = 108)

Total (n = 215, nRP = 867)

Completers (n = 163, nRP = 786)

Discontinuers (n = 45, nRP = 128)

Total (n = 208, nRP = 914)

B-S days (n)

17.1

32.4

19.0

20.0

27.6

21.1

B days (n)

 8.1

15.1

 9.0

12.5

14.2

12.8

B-S episodes (n)

 2.5

 3.6

 2.6

 3.1

 4.0

 3.3

Bleeding pattern indices (% of patients)

 Amenorrhea

20.7

 3.7

18.6

 5.1

 6.3

 5.3

 Infrequent B-S

27.2

24.1

26.9

21.9

17.2

21.2

 Frequent B-S

 6.0

16.7

 7.2

 4.3

22.7

 6.9

 Prolonged B-S

11.8

38.9

15.1

 9.4

20.3

10.9


B, bleeding; B-S, bleeding and/or spotting; nRP, number of 90-day RPs studied.
*Results represent mean of 90-day reference periods (RP) for all comparative studies between Implanon and Norplant.
Affandi B: An integrated analysis of vaginal bleeding patterns in clinical trials of Implanon®. Contraception 58 Suppl 1: 99S, 1998

 

Women considering implants should be informed that they are likely to experience changes in their menstrual pattern and that these changes are not a sign of ill health. Women who continue to find the spotting or bleeding troublesome even after reassurance may benefit from a number of medication interventions, including courses of oral ethinyl estradiol, levonorgestrel, nonsteroidal anti-inflammatory drugs,122,123,124 and combination OCPs.125,126 Studies also have found improvements with vitamin E supplementation127 and monthly mifepristone.128 Table 4 summarizes regimens used to treat prolonged or irregular bleeding. Combined OCPs appear to be more effective than ethinyl estradiol alone126 and have the advantage of easy availability. Unlike the oral estrogen, transdermal ethinyl estradiol did not significantly decrease bleeding.129 Irregular bleeding may recur after discontinuation of a course of any of these medications.

 

TABLE 4. Treatment of Prolonged or Irregular Bleeding in Contraceptive Implant Users: Regimens With Efficacy Demonstrated in Randomized Controlled Trials


Treatment

Prescribed For

Study Results

Combination Oral Contraceptive Pills

EE 50 μg/LNG 250 μg daily × 20 days*

Every bleeding episode longer than 7 days

67% stop bleeding within 3 days vs. 15% with placebo

86% stop bleeding within 7 days vs. 50% with placebo

EE 30 μg/LNG 150 μg daily × 21 days

Prolonged, frequent, or irregular bleeding by WHO criteria

Fewer days of bleeding, no change in number of episodes

18 days with treatment vs. 36 days pretreatment vs. 29 days with placebo during 90 days of study

EE Alone

EE 50 μg once daily × 20 days*,‡

Every bleeding episode longer than 7 days

Decreased bleeding each episode and throughout the year

91% stopped bleeding within 3 days vs. 15% with placebo

77 bleeding days per year with treatment vs. 129 days with placebo

EE 50 μg once daily × 21 days for prolonged

Frequent or irregular bleeding by WHO criteria

No change in number of episodes, fewer days of bleeding

19 days with treatment vs. 38 days pretreatment vs. 29 days with placebo during 90 days of study

Progestin Alone

LNG 30 μg twice a day × 20 days

Every bleeding episode longer than 7 days

Decreased bleeding each episode and throughout year

101 bleeding days per year vs. 129 days with placebo

Nonsteroidal Anti-Inflammatory Drugs

Ibuprofen 800 mg three times a day × 5 days

Every bleeding episode longer than 7 days

Decreased bleeding each episode and throughout year

77 bleeding days per year with treatment vs. 129 days with placebo

Mefenamic acid 500 mg twice a day × 5 days#

Every bleeding episode longer than 7 days’ duration or more frequent than every 16 days

76% ceased bleeding in 7 days vs. 27% with placebo

68% experienced a bleeding-free interval >20 days vs. 33% with placebo

Vitamin E Supplementation

Vitamin E 200 mg daily × 10 days, dose repeated after 30 days§

Frequent or irregular bleeding by WHO criteria

Decreased number of bleeding days during 2-mo study

7.7 days per month vs. 12.1 days per month with placebo

Monthly Mifepristone

Mifepristone 50 mg once monthly for 1yr.

Bleeding more than one episode every 24 days

Decreased frequency and duration of bleeding

No pregnancies in 100 women-years


EE, ethinyl estradiol; LNG, levonorgestrol; WHO, World Health Organization.
Compiled from multiple sources:
*Alvarez-Sanchez F, Brache V, Thevenin F, et al: Hormonal treatment for bleeding irregularities in Norplant implant users. Am J Obstet Gynecol 174, 1996
Witjaksono J, Lau TM, Affandi B, et al: Oestrogen treatment for increased bleeding in Norplant users: Preliminary results. Hum Reprod 11 (Suppl 2), 1996
Diaz S, Croxatto HB, Pavez M, et al: Clinical assessment of treatments for prolonged bleeding in users of Norplant implants. Contraception 42, 1990
#Kaewrudee S, Taneepanichskul S, Jaisamraun U, et al: The effect of mefenamic acid on controlling irregular uterine bleeding secondary to Norplant use. Contraception 60, 1999
§Subakir SB, Setiadi E, Affandi B, et al: Benefits of vitamin E supplementation to Norplant users—In vitro and in vivo studies. Toxicology 148, 2000
Cheng L, Zhu H, Wang A, et al: Once a month administration of mifepristone improves bleeding patterns in women using subdermal contraceptive implants releasing levonorgestrel. Hum Reprod 15, 2000

 

The pathophysiology of irregular bleeding is not fully understood. Erratic bleeding does not correlate clearly with serum concentrations of endogenous or exogenous steroids or with a particular pattern of endometrial histology. It appears that continuous exposure to progestin, in the presence of low to moderate levels of estrogen, results in an endometrium that exhibits “suppressed secretory” histology. Such changes are associated with disturbed angiogenesis, and the release of molecules capable of causing focal endometrial, epithelial, and endothelial damage and bleeding.130

NONMENSTRUAL SIDE EFFECTS

Other side effects observed in Norplant users include headaches, acne, mastalgia, weight changes, mood changes, anxiety, hirsutism, hyperpigmentation over the implants, ovarian cyst formation, and galactorrhea. Table 5 summarizes the adverse events reported in comparative trials of Implanon and Norplant. The relationship between reported adverse effects and implant contraceptives is difficult to establish. Although most of these side effects are mild in nature, and some may not be directly related to implants, they can cause women to discontinue the method. Women who use implants experience serious health complications at the same rate as the general population.11,111

 

TABLE 5. Drug-Related Adverse Events With Incidences of 5% or Greater for Implanon or Norplant in Comparative Studies


 

Women Reporting Adverse Event (%)

 

Implanon All Studies (n = 889)

Implanon Comparative (n = 184)

Norplant Comparative (n = 184)

Parameter

Drug-Related

Total

Drug-Related

Total

Drug-Related

Total

Acne

15.3

16.1

18.5

18.5

21.2

22.3

Breast pain

 9.1

10.6

 9.8

 9.8

11.4

12.5

Headache

 8.5

12.9

16.8

21.2

20.1

28.3

Weight increase

 6.4

 7.1

 6.5

 6.5

 7.1

 7.1

Abdominal pain

 4.3

 8.1

 8.2

11.4

 8.2

 9.8

Libido decrease

 2.9

 3.0

 3.3

 3.3

 5.4

 5.4

Dizziness

 2.9

 4.3

 6.5

 8.7

 7.1

 8.7

Injection site pain

 2.6

 2.8

 4.9

 4.9

 7.1

 7.1

Emotional lability

 2.5

 2.7

 4.9

 5.4

 7.6

 7.6

Influenza-like symptoms

 2.1

 6.9

 7.1

10.9

 4.3

13.6

Nausea

 2.0

 3.6

 3.3

 3.8

 5.4

 6.5


B, bleeding; B-S, bleeding and/or spotting; nRP, number of 90-day reference periods studied.
Adapted from Urbancsek J: An integrated analysis of nonmenstrual adverse events with Implanon®. Contraception 58[Suppl 1]: 99S

 

Weight Changes

About 30% of implant users note weight changes while using the method, weight gain being more common than weight loss. Reports are inconsistent, however. Seventy-five percent of levonorgestrel implant users in the Dominican Republic who experienced a weight change lost weight, whereas 66% in San Francisco gained weight. Weight gain may be explained by the androgen-related increase in appetite, but studies of implant users containing less androgenic progestins, such as etonogestrel, have demonstrated similar weight changes.131 Comparative trials have found no difference in weight gain between Norplant and Implanon users132 or between Norplant and nonhormonal IUD users.104

Mastalgia

Some implant users complain of breast tenderness, particularly just before bleeding. This symptom usually decreases with increasing duration of use and often responds to reassurance. For many women, wearing a more supportive bra is all that is needed.133 For the small percentage who do not respond to time, reassurance, and a supportive bra, effective medication regimens for mastalgia include a short course of evening primrose oil,134 tamoxifen (20 mg/day),135 danazol (200 mg/day),136 or bromocriptine (2.5 mg/day).137

Acne

Although acne has the highest reported incidence of all nonmenstrual averse reactions, there is little difference between the percentage of women who report acne before placement of implants and those reporting it at the time of removal, 24% versus. 21%. About 60% of women with pre-existing acne note improvement or resolution and 10% note worsening of the condition. Of women without acne at baseline, about 14% develop the problem while using implants.132 Progestins such as levonorgestrel produce a decrease in SHBG, leading to an increase in free androgens. Consequences of this change depend on both the degree of endogenous estradiol suppression and the inherent androgenicity of the progestin. Although Implanon contains a less-androgenic progestin and causes less suppression of SHBG, women using Implanon also report acne. Women who report increased acne should be taught good skin hygiene and usually benefit from application of topical benzoyl peroxide, salicylic acid, or antibiotics such as 1% clindamycin or erythromycin solution. Hair loss and acanthosis nigricans also have been reported as rare androgenic effects of levonorgestrel implants.

INDICATIONS

Contraceptive implants are appropriate for use by women of reproductive age who are sexually active and desire continuous, long-term contraception. The ideal user is a women who is unsatisfied with other reversible methods of birth control, is at risk for unintended pregnancy, and either is not ready for or wants an alternative to permanent sterilization. Implants should be considered particularly for women who have any of the following characteristics:

  • Desire a highly effective, long-term method of contraception
  • Experience serious or minor estrogen-related side effects with oral contraceptives
  • Have difficulty remembering to take pills every day, have contraindications to or difficulty using IUDs, or desire a non–coitus-related method of contraception
  • Have completed their childbearing but do not desire permanent sterilization
  • Have a history of anemia with heavy menstrual bleeding
  • Have risk factors for vascular disease that might be aggravated by exogenous estrogen (e.g. hypertension, smoking, family history of early stroke or heart attack)

CONTRAINDICATIONS

There are a few absolute contraindications to the use of progestin implants:

  • Active thrombophlebitis or thromboembolic disease
  • Undiagnosed genital bleeding
  • Acute liver disease
  • Benign or malignant liver tumors
  • Known or suspected breast cancer

Among the conditions that may preclude the use of combined OCPs but NOT progestin implants are:

  • Cigarette smoking in a women older than 35 years
  • Diabetes mellitus with vascular disease
  • Hypertriglyceridemia
  • History of stroke, heart attack, or deep vein thrombosis
  • Hypertension
  • Gallbladder disease
  • Vascular or migraine headaches
  • Depression

DRUG INTERACTIONS

Women considering implant contraception who take medications that increase the activity of microsomal liver enzymes (phenytoin, phenobarbital, carbamazepine, rifampin) should be advised that increased metabolism of progestin by these enzymes may lead to decreased blood progestin levels, increasing the risk of pregnancy. DMPA is a better choice than low-dose systems like implants because serum concentrations of the progestin are much higher with DMPA.

PROCEDURES FOR INSERTION AND REMOVAL

Insertion

Contraceptive implants may be inserted at any time during the menstrual cycle, immediately postpartum, or after an abortion. Pregnancy should always be excluded by menses, contraceptive history, or a negative pregnancy test. Practice with the “model arm” and coaching by an experienced clinician will result in symmetric subdermal placement that will enable easy removal of the implants. A description of both Norplant and Implanon insertion follows.

After providing counseling and obtaining written consent, position the woman comfortably in the supine position, with the shoulder extended to 90 degrees and the elbow flexed to expose the inner aspect of the upper arm. Select the site for placement 8 to 12 cm proximal to the medial epicondyle of the humerus in an area that is on the medial aspect of the arm (on the triceps, not the biceps) and unlikely to be visible when wearing short-sleeved shirts. When inserting six Norplant capsules, use a template as a guide to mark the skin over the site for the incision and points for the distal tips of the implants. Clean the area around the insertion with antiseptic solution and create a sterile field with a drape. Infiltrate the skin for a Norplant insertion with a total of about 6 mL 1% lidocaine with 1:100,000 epinephrine buffered with 1 mEq sodium bicarbonate per 10 mL lidocaine. When infiltrating the anesthetic, make sure it is placed just beneath the dermis in a fan shape, creating six channels to aid in placement of the implants. To insert a single implant like Implanon, simply raise a subdermal wheal of lidocaine with a tuberculin syringe.

For Norplant, use the No. 10 trocar with the obturator in place (or the scalpel, if the skin is tough), to pierce the skin and enter the subdermal space. The trocar has two marks along the length of the barrel to guide the placement of the implants. The first mark is close to the bevel and indicates how far the trocar should be retracted before redirecting it for placement of the subsequent implants. The second mark is close to the hub and indicates the distance the trocar must be inserted under the dermis before loading the implants for placement (Fig. 3).

Fig. 3. A. No. 10 trocar illustrating first (1) and second (2) markings to guide placement of implants. B. After infiltrating with local anesthetic, advance the trocar and obturator under the skin to the second mark nearer the hub.(Speroff L, Darney P: Long-acting steroid methods. In Fisher M [ed]: A Clinical Guide for Contraception. Baltimore, Williams & Wilkins, 1992)

Insert the Norplant trocar with the obturator in place up to the second mark. Remove the obturator and load the implant into the trocar, then gently replace the obturator until resistance is felt. Retract the trocar to the first mark while holding the obturator stationary to deposit the implant in the subdermal space the proper distance from the insertion site (Fig. 4). Redirect the trocar at an angle 15 degrees from the previous implant and repeat this procedure for placement of all six capsules (Fig. 5). After removing the trocar, place a finger over the incision and gently palpate the implants to document their location and ensure that their tips are at least 5 mm from the incision site. Reapproximate the skin with an adhesive strip and apply a pressure dressing to reduce bruising. The woman may remove the dressing after 24 hours. A diagram should be placed in the chart documenting the location of the implants as determined by palpation after the procedure. An accurate drawing will help locate the implants for future removal. The Implanon inserter is preloaded with the single contraceptive rod, easily pierces skin, and employs a withdrawal technique to deposit the rod subdermally (Fig. 6).

Fig. 4. Implant insertion. A. Once the trocar is inserted to the second mark, remove the obturator and place an implant in the trocar. B. Advance the obturator to the implant (to a point of gentle resistance). C. Withdraw the trocar to the mark nearer the tip, leaving the implant behind.(Speroff L, Darney P: Long-acting steroid methods. In Fisher M [ed]: A Clinical Guide for Contraception. Baltimore, Williams & Wilkins, 1992)

Fig. 5. Implant insertion. Redirect and advance the trocar and obturator while pushing the previously placed implant away from the trocar.(Speroff L, Darney P: Long-acting steroid methods. In Fisher M [ed]: A Clinical Guide for Contraception. Baltimore, Williams & Wilkins, 1992)

Fig. 6. Implanon inserter/trocar.(Herjan JT, Coelingh Bennink HJ: Introduction; Presentation of clinical data on Implanon. Contraception 58[Suppl 1]:75S, 1998)

COMPLICATIONS OF INSERTION.

Complications are uncommon and rarely serious. They include infection (0.8%), expulsion (0.4%), hematoma formation (<1.0%), and local irritation (temporary) (4.7%).138 Infection at the site usually occurs within the week after insertion but may occur up to 4 to 5 months later. These infections may be treated with oral antibiotics (e.g. dicloxacillin 250 mg, four times daily for 5 days) and local heat with the implants in place. However, one third of these infections are unresponsive to antibiotic therapy and require subsequent implant removal.138

If expulsion of one or more implants occurs, it usually happens shortly after insertion and is rare after the first few months of use. The primary causes of expulsion are concurrent infection and placement of the implants too close to the insertion site. If one implant is expelled without signs of infection, a new one can be inserted promptly. If infection is present, wait for resolution.

Removal

When a woman decides to have her implants removed and does not intend to conceive, plans must be made for another method of contraception before the removal because she may be susceptible to unwanted pregnancy within hours after the removal. Removal of implants is done with the patient under local anesthesia and may take from 2 to 60 minutes, depending on the number of implants, the skill of the practitioner, the depth of the implants, and the thickness of the surrounding fibrous sheaths.

Several techniques are available for removal of contraceptive implants. The original technique is described in the package insert for Norplant and uses a mosquito forceps to grasp the implant through the incision and a scalpel or second forceps to incise the fibrous sheath. In the U technique, a modified vasectomy clamp is used to grasp the implants, followed by scalpel incision of the fibrous sheath. The “fingers only” method, particularly appropriate for Implanon, uses finger manipulation and extrusion of the implant through a small incision, followed by scalpel incision of the sheath.139,140,141,142 Other methods have been reported; no one method is ideal for all situations.143,144 Some research suggests that the U technique may be preferable to the standard technique because of decreased complication rates, decreased removal times, and speedier training.140,145,146 The “fingers only” technique is less painful and produces a smaller scar but is applicable only when the implants are easily palpable.

STANDARD REMOVAL TECHNIQUE.

Position the woman as for insertion of the implants, clean the skin with antiseptic, and create a sterile field. Press down on the tips of the implants closest to the axilla to raise the distal (closest to the elbow) tips of the implants. This will identify the incision site over the implant that is most centrally located and equidistant from the other tips. Inject 1 to 2 mL buffered 1% lidocaine with 1:100,000 epinephrine under the tips of the implants at the incision site (Fig. 7). There is no need to inject additional anesthetic along the length of the capsules. Too much anesthetic makes palpation difficult. Make a 3- to 5-mm incision at the distal tip of the middle implant.

Fig. 7. Implant removal. Inject local anesthetic under the tips of the implants to be removed.(Norplant System: Levonorgestrel Implants. Vol. 2, Standard Removal Technique, p 7. Philadelphia, Wyeth-Ayerst Laboratories, 1995)

To remove the implants, the fibrous sheath encasing each capsule must be opened, preferably at the tip of each implant, where the implant wall is thickest. To extract the implants with instruments, open the subdermal space with the curved mosquito clamp. Grasp the tip of the implant closest to the incision and pull it into direct view at the incision (Fig. 8). Then, using a finger covered with an open gauze sponge, a straight mosquito clamp, or a scalpel, dissect away the fibrous sheath (Fig. 9). If the sheath is too dense to enter with the sponge or clamp, dissect it cautiously with the scalpel directly over the tip of the implant. Do not cut across the implant because you may inadvertently open or transect the capsule. Once the sheath is opened and the tip of the first implant is exposed, regrasp the exposed tip with the straight clamp. Release the first clamp and pull the implant out from the surrounding fibrous tissue (Fig. 10). If the implant cannot be brought into the incision with direct traction, redirecting the mosquito clamp anteriorly will help expose the implant. Repeat this procedure to remove all six implants, and show all the capsules to the woman to assure her they have all been removed. Close the incision with an adhesive strip and cover with a small dressing. If dissection was extensive, reduce bruising with a pressure dressing and an ice pack.

Fig. 8. Implant removal. Push an implant toward the incision and grasp its tip with the curved mosquito clamp.(Norplant System: Levonorgestrel Implants. Vol. 2, Standard Removal Technique, p 7. Philadelphia, Wyeth-Ayerst Laboratories, 1995)

Fig. 9. Implant removal. Lift up on the clamp and clean the fibrous sheath from the implant using a finger covered with an open sponge or gently with a scalpel.(Norplant System: Levonorgestrel Implants. Vol. 2, Standard Removal Technique, p 8. Philadelphia, Wyeth-Ayerst Laboratories, 1995)

Fig. 10. Pull the implant from the incision.(Norplant System: Levonorgestrel Implants. Vol. 2, Standard Removal Technique, p 8. Philadelphia, Wyeth-Ayerst Laboratories, 1995)

THE U TECHNIQUE.

Prepare the field and inject the anesthetic over the planned incision site parallel to and between the third and the fourth implants for Norplant and adjacent to a single implant. Make a 4-mm incision parallel to the implant and use the vasectomy clamp to grasp the nearest implant. Holding a fingertip on the skin surface against the implant can help guide it into the vasectomy clamp. Pull the implant into the incision by moving the handle of the clamp toward the patient’s head (Fig. 11) and clean the fibrous sheath with an open sponge or incise it with a scalpel to free the implant for removal (Fig. 12). Repeat this procedure to remove the other implants. Close the incision as described previously.

Fig. 11. Grasping the capsule in the U technique.(Norplant System: Levonorgestrel Implants. Vol. 3, Alternative Removal Techniques, p 8. Philadelphia, Wyeth-Ayerst Laboratories, 1995)

Fig. 12. Removal of the capsule using the U technique. A. With the jaws of the dissecting forceps open, impale the capsule shaft with one of the pointed forceps tips. B. Rotate the hand holding the dissecting forceps palm upward, so the forceps tips are facing upward with the implant still impaled. Close the dissecting forceps gently—just enough to hold the implant without cutting it—then release the ring forceps, allowing the implant to emerge from the incision.(Norplant System: Levonorgestrel Implants Vol. 3, Alternative Removal Techniques, pp 8–9. Philadelphia, Wyeth-Ayerst Laboratories, 1995)

THE “FINGERS ONLY” TECHNIQUE.

This approach is simple, causes little pain, and is especially applicable to one-implant (Implanon) and two-implant (Jadelle) systems.147 For six implants, a combination of fingers and instruments is often most efficient.

After positioning the patient’s arm and creating a sterile field as described previously, inject no more than 0.5 mL of local anesthetic directly at the tips of the implants. Make a 3-mm incision directly at the proximal tips of the most centrally located implants. Manipulate the implant tip into the incision with finger pressure until the fibrous sheath is visible. Maintaining this finger pressure on the implant with one hand to keep its tip visible in the incision, nick the sheath at the tip of the capsule with a No. 11 scalpel (Fig. 13). Once the sheath is opened, simply squeeze out the implant (Fig. 14). Repeat this procedure to remove the remaining implants through the single incision.

Fig. 13. Incise the fibrous sheath with repeated cuts across the tip of the implant.(Norplant System: Levonorgestrel Implants. Vol. 3, Alternative Removal Techniques, p 6. Philadelphia, Wyeth-Ayerst Laboratories, 1995)

Fig. 14. Push the implant out of its fibrous sheath and remove it.(Norplant System: Levonorgestrel Implants. Vol. 3, Alternative Removal Techniques, p 6. Philadelphia, Wyeth-Ayerst Laboratories, 1995)

COMPLICATIONS OF REMOVAL.

The most frequent complication of removal is difficulty feeling one or more of the implants. Impalpable implants can best be located with short-focus, high-frequency (7.5 mHz) ultrasonography or compression radiography (mammography).68,69 We have found sonography to be most efficient. The choice of method depends on which is most convenient at the institution. Real-time ultrasonography or fluoroscopy is rarely needed unless removal might pose a risk to neurovascular structures. Newer implants are packaged in an insertion trocar that facilitates proper insertion, rendering the problem of nonpalpable implants a less common concern. If an implant is broken during attempted removal, it may be necessary to make a second incision just over the end of the implant to remove the broken portion. It is better to make a second small incision than to enlarge a poorly situated one.

FUTURE OF IMPLANT CONTRACEPTION

The distributor of Norplant does not plan to reintroduce the six-capsule system. Jadelle is used in several countries but is not slated for marketing in the United States. Women in the United States can look forward to Implanon as the next implant option. Implanon has a different primary method of action (prevention of ovulation), uses a lower androgenic progestin, and may be the most effective reversible option available for women. One of the most important advantages of the one- or two-implant systems is the ease of placement and removal. Other single-implant systems such as Nesterone and Uniplant may be available in years to come. With so many new contraception options coming to market near the same time as the new improved implant—the vaginal ring, the skin patch, the levonorgestrel intrauterine system, the combined monthly injection—more women are likely to consider implants as one of several options and choose an effective method that suits their needs.

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