Implantable Contraception



Implantable Contraception


Rebecca Cohen, MD, MPH

Stephanie B. Teal, MD, MPH



The relatively high pregnancy rates with typical use of reversible contraceptive methods indicate the need for long-acting methods that are easier to use, with less dependence on frequent, perfect actions by the user. Implantable, subdermal capsules that release progestins for several years are a response to this need.

Historically, the first widely used contraceptive subdermal implant system was the Norplant levonorgestrel system, consisting of six Silastic (silicone elastomer) tubes containing crystalline levonorgestrel. Although manufacturing of Norplant ceased in 2008, providers may still encounter women using this method. Jadelle is a two-rod levonorgestrel system, which utilizes Silastic rods slightly longer and thicker than those of the six-rod Norplant system. In many parts of the world, Jadelle replaced the use of Norplant. A Chinese version of Jadelle, called Sinoplant II/Levoplant, also consists of levonorgestrel 150 mg contained in two rods. Jadelle is approved by the U.S. Food and Drug Administration but has not been marketed in the United States.

The other widely available implant system is Nexplanon/Implanon NXT, a single-rod implant containing a different gonane progestin, etonogestrel (3-ketodesogestrel) (Figure 5.1).1,2 The implant was originally marketed as Implanon and then Nexplanon/Implanon NXT following changes in the inserter and addition of barium sulfate to make the implant radiopaque (Figure 5.2). Like Norplant, Nexplanon has been extensively marketed throughout the world with excellent safety and efficacy and high continuation rates. Contraceptive implants are approved in more than 60 countries and are used by millions of women worldwide. However, use of other methods (permanent contraception, intrauterine device [IUD], or oral contraception) is far more prevalent than implant use in most countries.3

The long-acting implantable progestin methods prevent pregnancy at rates similar to permanent contraception and IUDs and more effectively than oral and barrier contraception.4 An important reason for this high efficacy in actual use is the nature of the delivery systems themselves, which require little effort on the part of the user. Because compliance does not require frequent resupply or instruction in use, as with oral, injectable, or barrier contraception, the actual or typical use effectiveness is very close to the theoretical (highest expected) effectiveness. In developing countries, the single act to
provide years of contraception also eliminates supply chain issues related to ensuring repeated availability of shorter-acting contraceptives.






Figure 5.1 Etonogestrel Single-Rod Implant.

Sustained-release methods require less of the user but demand more of the clinician. The implant is relatively new compared to other methods, and women may be hesitant to consider its use. Implants involve minor procedures for placement and removal. Clinicians have a special responsibility to become skillful in the operations required to place and remove implants and to be available to women when those skills are required to discontinue use. Disturbances of menstrual patterns and other side effects may require more counseling and follow-up than other contraceptive methods.5,6


Implant Systems


Levonorgestrel

Norplant was developed by the Population Council and first approved in 1983 in Finland, where it was manufactured. It was approved in the United
States in 1990, marketed in 1991, and withdrawn from the U.S. market in a 2002 business decision dictated by profit and liability despite the fact that it provided an excellent option for contraception. In 2008, manufacturing of Norplant ceased.






Figure 5.2 Nexplanon inserter.

Jadelle was also developed by the Population Council and manufactured in Finland. It was approved in the United States in 1996, but never marketed. The thin, flexible Jadelle rods are wrapped in Silastic tubing, 43 mm in length and 2.5 mm in diameter.7 Each rod contains 75 mg levonorgestrel for a total of 150 mg. Whereas Norplant contained crystalline levonorgestrel inside a silicone capsule, the core of the Jadelle rod is a mixture of levonorgestrel and an elastic polymer (dimethylsiloxane/methylvinylsiloxane). The initial levonorgestrel release rate is 100 µg daily, which decreases to 40 µg daily at 1 year and 30 µg daily at 2 years, rates similar to Norplant.7 Longterm clinical trials indicate that the performance and side effects are similar to Norplant, but insertion and removal are faster.8,9 Because the release rates with the two levonorgestrel systems are comparable, it is reasonable to conclude that the results from clinical studies with Norplant and Jadelle should be considered interchangeable.


Etonogestrel

Implanon is a single flexible rod, 4 cm long and 2 mm in diameter, that contains 3-ketodesogestrel (etonogestrel, the active metabolite of desogestrel) 68 mg dispersed in a core of ethylene vinyl acetate wrapped with a 0.6-mm-thick membrane of the same material. It was introduced in 1998 and approved in the United States in 2006. Nexplanon/Implanon NXT (approved in the United States in 2011) is bioequivalent to Implanon.10 There is no evidence that either ethylene vinyl acetate or Silastic has toxic effects when implanted.11 The hormone is released at an initial rate of about 67 µg/d decreasing to 30 µg after 2 years; concentrations that inhibit ovulation are achieved within 8 hours of insertion.12 A steady state is achieved after 4 months, after which there is a gradual decline.12 Side effects are similar to those of the levonorgestrel implants, except for less bleeding and a higher rate of amenorrhea with the etonogestrel implant.13,14

In the United States, the etonogestrel implant is FDA approved for up to 3 years of use as a contraceptive method.15 The etonogestrel implant suppresses ovulation for at least 2.5 years and provides effective contraception for much longer. Among more than 300 women using etonogestrel implants for at least 5 years in research settings, there were no additional pregnancies in the 4th or 5th year of use.16,17,18 Women and providers can be reassured that an “expired” implant (used beyond 3 years’ duration) can provide effective contraception for several additional months. For women who desire contraception for more than 3 years, extended use of the implant could improve safety (fewer removals/insertions), decrease annual cost of use, and lessen burden on health care systems.18




Mechanism of Action

Hormone release rates from contraceptive implants are determined by total surface area and the progestin density of the polymer. The progestin diffuses from the implant into the surrounding tissues where it is absorbed by the circulatory system and distributed systemically. Within 8 hours after etonogestrel implant insertion, etonogestrel plasma concentrations are about 300 ng/mL, high enough to prevent ovulation.21 About 90% of women will demonstrate
unfavorable cervical mucus preventing sperm penetration within 3 days when the levonorgestrel implant is inserted just prior to ovulation (during days 8 to 13 of the menstrual cycle)22; however, this is not a reliable marker of in vivo contraceptive effect.23 There are no in-depth studies of timing of cervical mucus changes after etonogestrel implant insertion.23 Throughout the duration of implant use, serum levonorgestrel concentrations show much wider within-group variation than serum etonogestrel concentrations (Figure 5.3).21






Figure 5.3 Variation in serum levels seen with use of contraceptive implants. Serum concentrations of etonogestrel (solid line) and levonorgestrel (dashes) during the first 4 weeks after implant insertion. Boxes represent the P25-P75 range; T bars represent the minimum and maximum concentrations. Median values are connected. (From Makarainen L, van Beek A, Tuomivaara L, Asplund B, Coelingh Bennink H, Ovarian function during the use of a single contraceptive implant: Implanon compared with Norplant, Fertil Steril 69(4):714-721, 1998. Copyright © 1998 Elsevier. With permission.)

The etonogestrel implant releases 60 µg per 24 hours at 3 months of use. This rate declines gradually to 40 to 50 µg daily by 12 months and 30 µg/d by 2 years of use.21 The two-rod levonorgestrel implant releases 100 µg daily during the first few months of use, about equivalent to the daily dose of levonorgestrel delivered by the progestin-only oral contraceptive and 25% to 50% of the dose delivered by low-dose combined oral contraceptives (see Figure 2.13 in Chapter 2). After 6 months of use, daily levonorgestrel concentrations are about 0.35 ng/mL; at 5 years, the levels decrease to 0.29 ng/mL.24 Until the 8-year mark, mean levels remain above 0.25 ng/mL.25



Advantages

Implants provide a safe, highly effective, continuous method of contraception that requires little user effort. Because this is a progestin-only method, it can be used by women who have contraindications for the use of estrogencontaining contraceptives. The sustained release of low doses of progestin avoids the high initial dose delivered by injectables and the daily hormone surge associated with oral contraceptives. Another advantage of the implant
method is that it allows women to plan their pregnancies precisely; return of fertility occurs rapidly; etonogestrel serum levels are undetectable within 1 week after removal of the implant, and ovulation can be expected in the 1st month after discontinuation.12,21

One of the major advantages of sustained-release methods is the high degree of efficacy, nearly equivalent to the theoretical limit of effectiveness. In couples for whom elective abortion is unacceptable in the event of an unplanned pregnancy or for women who are at high risk of medical complications with pregnancy, the high efficacy rate is especially important. There are no forgotten pills, broken condoms, lost diaphragms, expelled rings or IUDs, or missed injections.

Exposure of endometriosis to systemic progestin-only contraceptive methods is an effective method to manage the pain associated with this condition. Nexplanon, along with other progestin-containing methods, can improve symptoms of endometriosis.45,46,47 Nexplanon may have an advantage over levonorgestrel intrauterine systems for women who benefit from ovulation suppression, such as those with severe premenstrual dysphoric syndrome, menstrual migraines, or catamenial seizures.


Disadvantages

Implants cause disruption of bleeding patterns (see Menstrual Effects section), especially during the first year of use, and some women or their partners find these changes unacceptable.48 Cultural factors can influence the acceptability of menstrual changes. Some cultures restrict a woman from participating in religious activity, household activities, or sexual intercourse while menstruating. All users must be aware of the possible menstrual changes. It is important to stress that menstrual changes are expected, that they do not cause or represent illness, and that many women revert back to a more normal pattern with increasing duration of use.

Women cannot initiate or discontinue implants without the assistance of a trained clinician. Women also need to understand that implants may be noticed under the skin of the upper arm when elevated and externally rotated or when the area is touched. This sign of the use of contraception may be unacceptable for some women and for some partners.6,49 However, we strongly recommend against deep placement to hide contraceptive use, due to the potential for neurovascular injury, migration away from the insertion site, or difficulty removing a deeply placed implant.

Like other hormonal methods, implants do not provide protection against sexually transmitted infections (STIs) such as herpes, human papillomavirus, HIV, gonorrhea, or chlamydia. Implant users may be less likely to use condoms because they do not see a need for additional contraceptive protection due to the high efficacy of the implants50,51,52,53; those at risk for STI acquisition should be reminded to use condoms to prevent infection.

Because the insertion and removal of implants require minor procedures, initiation and discontinuation costs are higher than with oral contraceptives or barrier methods. The cost of implants plus fees for insertion may seem high to patients unless they compare it with the total cost of using
other methods for up to 5 years.54,55 Many women do not use long-acting methods for their full duration of action, for reasons ranging from personal preference to desire for pregnancy and to dissatisfaction with side effects. Short-term implant use is expensive compared with the relatively low initial costs of other reversible methods; however, the etonogestrel implant is costeffective at nearly all time points when the cost of unintended pregnancy is considered.56,57 Clinicians should offer the full range of contraceptive options for women and support policies that remove the cost barrier to long-acting reversible contraceptive (LARC) methods.

Insertion and removal of implants will be a new experience for most women. As with any new experience, women may approach it with varying degrees of apprehension. We encourage prospective users to see and touch models of implants. Women should be told that an implant is not inserted with an incision, just a very small needle entry site that heals quickly, leaving small scars that are usually difficult to see because of their location and size. Women can be reassured that the implant will not be damaged or move if the skin above the implant is accidentally injured. Normal activity will not damage or displace the implants. Most women become unaware of their presence. A few women report sensing the implants if they have been touched or manipulated for a prolonged period of time or after vigorous exercise. The implants are more visible in slender women with good muscle tone. Darker-skinned users may notice further darkening of the skin directly over the implants; this resolves after removal. Implants may rarely break after excessive manipulation. This does not change efficacy and does not necessitate removal.


Efficacy

Contraceptive implants provide highly effective birth control. In 2- and 3-year studies in 11 international clinical trials of 942 women using the etonogestrel implant, no pregnancies occurred.35 In studies of Norplant conducted in 11 countries, totaling 12,133 woman-years of use, the pregnancy rate was 0.2 pregnancies per 100 woman-years of use.58 If luteal phase insertions are excluded from analysis, the first-year pregnancy rate drops to 0.01 per 100 woman-years. In adolescents, implants provide better protection against unwanted pregnancy than do oral contraceptives.59,60,61

There are no weight restrictions for levonorgestrel implant users, but heavier women (more than 70 kg) may experience slightly higher pregnancy rates in the later years of use compared with lighter women. The differences in pregnancy rates by weight are probably due to the dilutional effect of larger body size on the low, sustained serum levels of levonorgestrel. Heavier women should not rely on Jadelle beyond the 5-year limit. For slender women, the duration of efficacy extends well past the 5th year of use. In an extended-use trial, rare pregnancies were reported into the 7th year.62

The contraceptive efficacy of the etonogestrel implant surpasses that of Norplant, Jadelle, and permanent contraception using occlusive or partial
salpingectomy procedures.2 Pregnancy rarely occurs, resulting in a Pearl Index of less than 0.01.42,63 In over 70,000 cycles, no pregnancies were recorded because of total inhibition of ovulation until the last 6 months of the 3-year period.41,64 Postmarketing surveillance of pregnancies in Australia, where nearly one quarter of contraceptors relied on Implanon in 2004, revealed that of 218 pregnancies, only 13 could possibly have been failures of the method.65 Instead, pregnancies had occurred before insertion or resulted from failure to correctly insert the implant. While pregnancy in implant users is rare, it should be considered if there are concerns for an early (undetected) pregnancy at the time of implant insertion, if there is suspicion for improper insertion or noninsertion of the implant (i.e., if implant is not palpable immediately after insertion), or if the patient is taking a medication that can reduce the effectiveness of the implant. A sensitive urine pregnancy test should be obtained in these settings or if a woman reports symptoms consistent with pregnancy. Women who remain amenorrheic throughout their use of implants are unlikely to become pregnant.66


Ectopic Pregnancy

Due to the fact that overall pregnancy rates among contraceptive implant users are so low, ectopic pregnancies are extremely rare. Studies of levonorgestrel two-rod systems have found ectopic pregnancy rates of 0.2 to 0.8 per 1,000 women-years. Ectopic pregnancies represent around 20% of all pregnancies reported.67 There are fewer studies including etonogestrel implant users; because pregnancies are exceedingly rare, there are no stable estimates of the risk of ectopic pregnancy should pregnancy occur. Should a pregnancy occur in a woman using the etonogestrel implant, we recommend ruling out ectopic pregnancy.65,67


Menstrual Bleeding Effects

Menstrual bleeding patterns are highly variable among users of implant contraception. The simple and concise caveats are that all progestin implants cause unpredictable/irregular bleeding. With levonorgestrel implants, the bleeding generally becomes more regular over time for many women. With the etonogestrel implant, bleeding usually remains irregular over the course of use but tends to be light and tolerable. Women using the etonogestrel implant who initially experience amenorrhea or infrequent bleeding are very likely to maintain a good pattern over the ensuing year.

Among levonorgestrel implant users, the changes include alterations in the interval between bleeding, the duration and volume of menstrual flow, and spotting. About 10% of users experienced amenorrhea for at least 90 consecutive days in the first year of use, and about 20% reported normal menstrual bleeding patterns. Users reported a mean of 20 days of bleeding or spotting per 90 days of use in the first year.68 After 2 years, ovulation occurs in about half of the menstrual cycles among levonorgestrel implant users,21 so bleeding may become more regular. Although bleeding problems occur much less frequently after the 2nd year, they can occur at any time.66,69
With continued use, the endometrium of implant users becomes atrophic with enlarged fragile venous sinusoids.70 In a study of 60 levonorgestrel and etonogestrel implant users, none showed hyperplastic or metaplastic changes.71 Within weeks after insertion, the density of endometrial small blood vessels increases, and the endometrium regresses to an atrophic state.72 Abnormal bleeding may result from decreased endometrial perfusion

causing proliferation of less-stable, highly permeable endometrial vessels.73 The etonogestrel implant alters bleeding patterns in an unpredictable manner. In a large clinical study that assessed bleeding across several 90-day “reference periods,” women experienced a median 13 to 16 days of bleeding or spotting per reference period, with no consistent improvement or worsening over time. Women who experienced favorable bleeding patterns early in use (0 to 28 bleeding or spotting days in the reference period beginning 1 month after implant initiation) were likely to continue with a favorable bleeding pattern. Women with unfavorable bleeding patterns had approximately a 50% chance of attaining a favorable bleeding pattern if they did not discontinue use.5 A single etonogestrel implant suppresses ovulation reliably for most women for 2.5 years, and, therefore, menses do not become more regular over time. Bleeding is lighter and less frequent among etonogestrel implant users than among levonorgestrel implant users because more profound ovarian suppression results in less follicular estrogen production and less endometrial stimulation; nevertheless, irregular bleeding continues to be a major reason for discontinuation.5,74

Despite an increase in the number of spotting and bleeding days over preinsertion menstrual patterns, hemoglobin concentrations do not decrease in etonogestrel or levonorgestrel implant users because of a decrease in the average amount of menstrual blood loss.75,76,77

If a woman presents with concerns of heavy or otherwise concerning bleeding, we recommend ruling out other potential causes of bleeding such as pregnancy, infection, fibroid/polyp, and anticoagulation. Those at risk of STIs (e.g., in a new relationship and not using a barrier method) should be appropriately evaluated. Women due for cervical cytology screening should receive this testing as part of the evaluation of unscheduled bleeding.78

Implant users who can no longer tolerate bothersome bleeding may benefit from a short course of estrogen to stabilize the endometrium, although bleeding typically returns quickly after pills are stopped.79,80 The irregular bleeding patterns noted in implant users confound investigation of effective therapies for bleeding, as many women who received placebo rather than estrogen-progestin oral contraceptives in a randomized controlled trial also experienced improvement of bothersome bleeding within 1 month.80 For women without contraindications to estrogen, we recommend use of a combined oral contraceptive pill for short-term treatment (10 to 20 days).81 No specific formulation has been shown to be superior, but we recommend starting with a pill that contains ethinyl estradiol 30 or 35 µg. If women desire longer-term bleeding control, combined oral contraceptives can be used along with the implant continuously (with typically fewer overall bleeding
days but less predictability) or with a placebo week to allow for more predictable withdrawal bleeding. In a prospective cohort study of 20 women using the etonogestrel implant as backup to combined oral contraceptives, most participants reported infrequent or irregular bleeding.82 By 6 months after initiation, two women requested implant removal (not for bleeding complaints) and seven women had discontinued use of oral contraceptives; of participants continuing concurrent use of both methods, most reported unchanged or improved bleeding patterns.82 Nonsteroidal anti-inflammatory drugs can improve bleeding by inhibiting cyclooxygenase.83 Mefenamic acid 500 mg orally three times daily for 5 to 7 days decreased subsequent bleeding over the next 28 days in etonogestrel implant users (10.5 bleeding days vs. 16.8 bleeding days in women who received placebo).84 In levonorgestrel implant users, celecoxib 200 mg orally daily led to both faster cessation of a bleeding episode (70% stopped bleeding within 7 days vs. 0% in the placebo group) and a longer bleeding-free interval after cessation (24 vs. 10 days).85 As both of these medications require a prescription for use, providers can also consider use of over-the-counter alternatives ibuprofen (800 mg three times daily for 5 days) or naproxen (500 mg twice daily for 5 days).83 Tamoxifen86 and tranexamic acid83 (used separately) each show promise as a method of improving implant-related bleeding patterns in the short term. In the randomized trial of tamoxifen, women who received 10 mg twice daily for 7 days reported 5 fewer days of bleeding/spotting over 30 days (95% confidence interval [CI] −9.9 to −0.05), and 15.2 more continuous bleeding-free days (95% CI 2.8-27.5 days) after first use of study drug.86 Results of using doxycycline (as a matrix metalloproteinase inhibitor) to improve bleeding have been mixed, and mifepristone can improve bleeding but is difficult to obtain and may compromise contraceptive efficacy.83 A small study of ulipristal acetate versus placebo (used daily for 7 days) showed increased satisfaction and decreased bleeding in the 30 days following use (median 12 days of bleeding for placebo and 7 days for ulipristal acetate).87


Metabolic Effects

Exposure to the sustained, low doses of progestin delivered by the implants is not associated with significant metabolic changes. Studies of liver function,88,89,90 blood coagulation,91 immunoglobulin levels,92,93 serum cortisol levels,38,94,95 lipoprotein profile,77,90,96,97,98 carbohydrate metabolism and insulin sensitivity,90,97,98,99 inflammatory markers,100 thyroid and adrenal function,101 and blood chemistries102,103 have failed to detect clinically significant changes outside of normal ranges in healthy levonorgestrel or etonogestrel implant users. Blood pressure does not change significantly with implant use.98 Insulin-treated diabetics did not show worsening of carbohydrate metabolism, lipid metabolism, or microvascular lesions during 2 years of etonogestrel implant use.104

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Mar 1, 2020 | Posted by in OBSTETRICS | Comments Off on Implantable Contraception
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