Subdermal progestin implants are a recent addition to the extensive armamentarium of contraceptive options available today. Because they offer unique advantages, they have continued to be widely used since their introduction. However, their side effects, mainly irregular bleeding and occasional challenging removals, have made this form of contraception unacceptable to a significant minority. Norplant is the only subdermal implant currently available in the United States; therefore, this discussion mostly focuses on it. Other types of implants available abroad and in development are also introduced.
The research into the development of a long-acting subdermal implant began in the 1960s. 1 Silicone rubber was initially selected for the capsule because of its previously demonstrated safety in products such as heart valves, drainage tubes, and Falope rings, and its ability to release lipophilic compounds, such as steroids, at a slow and steady rate. Next, levonorgestrel was chosen to be the progestin because of its previously demonstrated safety in oral contraceptive pills and its extremely slow rate of release. 1 In 1983, Finland was the first country to approve the system. Many others did so as well soon after, and in December of 1990, the Norplant system was approved for use in the United States. By 1994, more than three million women around the world were using the implants. 1,2
Since its introduction, Norplant has been the subject of controversy focusing mainly on its side effects, requirement of trained professionals for insertion and removal, and coercive application of the method toward low-income and other unempowered groups. 3 More than 50,000 claims have been filed against the manufacturer, Wyeth-Ayerst Laboratories (Radnor, PA). 4 All of the court decisions awarded have been in favor of the manufacturer: three jury verdicts, 20 summary judgments before trial, and approximately 14,000 dismissals. The remainder of the lawsuits were settled out of court in 1999. Whereas ultimately it was found that Norplant was a safe and effective method of contraception, the settlement compensated women for poor counseling procedures before the use of Norplant. Some women did not fully understand the potential side effects of Norplant, and it was thought that the company minimized these potential side effects. It is important to note, however, that no court of law has ever found that Norplant was not safe or that it was not effective. The Food and Drug Administration (FDA) has also reaffirmed that Norplant is safe and effective. 4
Despite approval and support by leading groups, including the American College of Obstetricians and Gynecologists, the American Society for Reproductive Medicine, the Planned Parenthood Federation of America, and the American Medical Association, this controversy had tainted Norplant’s public image and launched further research of the method. 3,4 In the face of overwhelming positive findings about high levels of satisfaction among its users, the system’s use in the United States has decreased, so that in 1995, only approximately 1.5% of contraceptive users were using Norplant. 5 Whereas the company announced plans to continue the product in the U.S., in the United Kingdom, the company discontinued Norplant because of similar litigation and negative publicity.
Norplant is a subdermal implant, which is a progestin-only, long-acting, reversible method of contraception for women. The system consists of six rods, 34-mm long, and 2.4 mm in diameter. The capsules are made of silastic (polydimethylsiloxane and methyl vinyl siloxane copolymer) tubing. Each capsule contains 36 mg of crystalline levonorgestrel. 5 The product is heat-sealed in pouches that can be safely stored for up to 5 years. The system has been shown to deliver adequate levels of levonorgestrel for up to 7 years, and it is currently approved for up to 5 years of use.
The implants release approximately 80 μg of levonorgestrel per 24 hours during the first year of use, achieving effective serum concentrations of 0.4 to 0.5 ng/ml within the first 24 hours. The rate of release decreases to 30 μg per day in the latter years of use. These 80 μg per day are approximately equivalent to 25–50% of the dose provided by a low-dose combined oral contraceptive pill and are approximately equal to the daily dose of a progestin-only oral contraceptive. 6 This steady concentration is maintained throughout 5 years of use, more than the 0.20 ng/ml level, below which pregnancy rates increase.
MECHANISM OF ACTION
Levonorgestrel affects the female reproductive system in several ways. It is probably the combination of all these actions that results in its high contraceptive efficacy. The progestin acts on both the hypothalamus and the pituitary gland to suppress the release of gonadotropins. 2 The effect is particularly strong on the luteinizing hormone and prevents its surge, which is responsible for ovulation. The degree of influence depends on serum concentration of levonorgestrel. Thus, in the initial months when the concentration is highest, only approximately 10% of the women are ovulatory. Toward the fifth year of use, however, more than 50% are ovulatory. 2,7
Levonorgestrel also exerts a powerful effect on the cervical mucus. The mucus thickens and decreases in quantity, thus forming a barrier to sperm. 2 Finally, constant presence of the progestin prevents the cyclic maturation of the endometrium. This results in atrophic endometrium, which is inhospitable to implantation. However, it is important to note that fertilization rarely occurs, and therefore, the latter mechanism has a minor role. 2
In summary, progestin implants likely suppress the initiation of folliculogenesis at the level of the hypothalamus at high concentrations. At slightly lower concentrations folliculogenesis is initiated, but the progestin acts on the pituitary gland to prevent the luteinizing hormone surge and, therefore, to prevent ovulation. At even lower concentrations, ovulation is often not suppressed, and the contraceptive mechanism of progestin is to alter cervical mucus, tubal motility, and/or the endometrium. 8
Norplant is a highly effective contraception method. Because the efficacy does not depend on the user, the typical pregnancy rates closely approximate the theoretical. Many large studies have been performed, reporting a cumulative 5-year pregnancy rate between 0 and 4.2 per 100 women, 9 with an average pregnancy rate of 0.2 per 100 woman-years use. 6 Unfortunately, most of these studies were performed before 1990 and mostly outside of the United States. Until the early 1990s, two types of silicone tubing were used to form the capsule of the implants: hard and soft. In the late 1980s, it was demonstrated that the soft tubing allowed for more levonorgestrel to be released in the later years of use, thereby increasing serum concentrations and achieving lower pregnancy rates in the third through fifth years. 10
Since then, only the soft-tubing implants have been manufactured in the United States; however, the reported pregnancy rates frequently use data from the older or foreign studies that included patients using the hard-tubing implants. A large, recent study in the US reported on 511 women using soft-tubing implants who were followed-up for 5 years. 10 This study showed a cumulative five-year pregnancy rate of 1.3 per 100 women. The first accidental pregnancy occurred at month 35 in a patient using rifampin. Two other pregnancies occurred in the fifth year. Thus, it appears that the current product rivals the efficacy of sterilization.
Several factors have been identified to affect Norplant’s efficacy. Because the serum levels of levonorgestrel are low, any factor that further decreases the progestin concentration may lower it below the effective range. Drugs that accelerate hepatic microsomal metabolism have been shown to reduce the system’s efficacy by accelerating clearance of levonorgestrel. 5,6 These include phenobarbital, rifampin, phenytoin, and carbamazepine.
If pregnancy does occur while using Norplant, it has a greater chance of being ectopic than it would if conception had occurred without any contraception. Studies have shown as many as one-third of pregnancies that occur during the use of Norplant may be ectopic. 10 However, given the low pregnancy rate, the absolute risk of ectopic pregnancy is exceedingly low, at approximately 0.6 per 1,000 woman-years.
Insertion of the implants should be performed by practitioners adequately trained in the technique. Pregnancy must be ruled out before initiation of the contraceptive. Ideally, insertion should occur within the first 7 days of the menstrual cycle. This would greatly diminish the risk of pregnancy and avoid the need for back-up contraception. Initiation may safely take place in the postpartum period. 11
Proper technique is essential because correctly placed implants usually lead to easy removals, whereas removing poorly placed implants can be extremely challenging. Insertion is simple and takes 5 to 15 minutes. Detailed instructions are provided in the package insert. The implants should be placed in the inner aspect of the nondominant arm, approximately 8 to 10 cm above the elbow crease in a fan-like pattern. A small incision is needed, not more than 2 to 4 mm. An alternative technique does not require a scalpel and uses the trocar to simply puncture the skin. 12 To facilitate removal, all implants should be placed close to the skin within the same plane. To close the incision, no sutures are required. An adhesive strip is used to appose the skin edges, and a pressure dressing is used to minimize bleeding.
Complications of insertion are usually minor and easily treated. Local reactions are not unusual. In one study, which specifically examined this issue, 1 week after insertion, ecchymosis was present in 31–33%, edema/swelling in 12–14%, tenderness in 31%, defective scar in 2%, and pain in 9–11%. 12 At 30 days after insertion, the incidence of all signs and symptoms decreased to 1% or less, except local tenderness, which was 3–4%. Most studies have reported infection rates to be less than 1%. 2 Most are successfully treated with antibiotics, but some require removal of the implants. Expulsion of an implant rarely occurs. Occasionally, an allergic reaction to the anesthetic, adhesive, antiseptic, or dressing is seen. The risk of these complications can be minimized by use of strict aseptic technique and adequate clinician training. Hematoma/ecchymosis formation can be limited with a good pressure dressing.
In most patients, removal is simple and requires 15 to 20 minutes. 13 However, in as many as 6% of women, removal is difficult and may require more than 1 hour. The standard removal technique was developed by the Population Council in the 1980s and published in the World Health Organization guidelines in 1990. 13 This technique uses a 4-mm incision at the base of the capsules. A curved mosquito clamp is used to grab the fibrous sheath that has formed around each capsule and to pull it into the incision. The fibrous sheath is then dissected with a straight mosquito clamp or scalpel. The implant is visualized, grasped, and delivered through the incision.
The most common complications encountered during removal are broken implants (1.7%) and implants embedded below the subdermal plane (1.2%). 13 Other complications include displaced implants, pain during removal, and bleeding. It was also found that infection, at the time of insertion or removal, was a major risk factor for a complicated removal. In an effort to simplify removal, decrease incidence of complicated removals, and shorten removal time, several alternative removal techniques have been developed. 13 Darney 13 described a “pop-out” method that uses the clinician’s fingers to push the implants out of the incision. The Emory method relies on a larger incision for more rapid removal. Finally, the “U” technique places the incision in the center of the implants and relies on a modified holding forceps. Each method has unique advantages and disadvantages, and neither has been shown to be obviously superior. Each clinician should be proficient in one or more of these techniques. Clearly, the most important factors in facilitating removals are proper insertion and adequate clinician training.
When difficult removals are encountered, several strategies have been recommended. If removal is taking more than 30 minutes, the procedure can be terminated and the remaining implants removed several weeks after swelling has subsided. If an implant cannot be located, ultrasound or standard radiography can be used to correctly identify its position. Rarely, a second incision is required to reach a capsule that has migrated, broken, or bent.
Mild side effects are reported by most patients, but they are usually well tolerated. The most common of these is menstrual irregularity. Changes in bleeding patterns are reported by 60–80% of patients in most studies. 10,14 Menstrual irregularities, in order of reported frequency, include prolonged bleeding, spotting, irregular onset of bleeding, and amenorrhea. The incidence of bleeding irregularities greatly diminishes after the first year of use. 10 Approximately one-third of women will continue to have regular cycles after initiation of use, and this group increases to two-thirds by the fifth year of use. Importantly, studies with other implants have demonstrated that the bleeding irregularities induced by these methods do not affect sexual desire, frequency of sexual activity, or sexual enjoyment for women or their partners. 15
Several authors have reported that although the number of bleeding days increases with initiation of Norplant, excessive blood loss does not occur, and hemoglobin concentrations are not affected. 16 If the number of bleeding days or the menstrual flow is excessive, estrogen can be temporarily added to effectively treat the problem. 17 Alternatively, administration of mefenamic acid (a nonsteroidal antiinflammatory) at a dose of 500 mg twice per day for 5 days has been shown to be effective for short-term control of irregular bleeding. 17
Weight change is a side effect that is frequently assigned to all hormonal contraceptives. Studies of weight change in Norplant users have been contradictory. Sivin et al 10 reported that after the first year of use, 28.5% lost weight, whereas 59.2% gained an average of 1.5 kg. In this study, after 5 years, the mean weight change was a gain of 5.2 kg. Several other American studies have also reported modest continuous weight gain. However, when compared with a control group (intrauterine device users), similar weight gains were observed. 18 Thus, it is not clear whether Norplant is responsible for a small weight gain or if the gain is caused by confounding factors in American society.
The incidence of simple ovarian cysts is increased in Norplant users. As described previously, the low serum concentrations of progestin suppress the luteinizing hormone surge in a large fraction of women and thereby prevent ovulation. However, these levels of levonorgestrel do not appear to suppress the release of follicle-stimulating hormone, which continues to stimulate follicular growth in some of the users. Studies of ovarian endocrine function reveal that approximately one-third of women exhibit prolonged estradiol increases more than 400 pg/ml. 7 Thus, these women have follicles develop, with the influence of follicle-stimulating hormone, which do not ovulate and may continue to grow. This phenomenon has been well described in users of other progestin implants. 8 Most of these are asymptomatic and self-limited, but some may cause pain, undergo painful rupture, or, rarely, cause ovarian torsion.
The list of side effects reported by Norplant users also includes: headaches, mood changes, nervousness, dizziness, nausea, facial hair growth, hair loss, acne, mastalgia, galactorrhea, and hyperpigmentation covering the area of implants. 10,14 Most of these are mild and alleviated with reassurance and symptomatic relief. The symptoms will usually decrease with longer duration of use. 10 Serious complications such as pulmonary embolism, stroke, and myocardial infarction have been reported in Norplant users. However, no evidence exists that the incidence of these events is increased, and a causative relationship is not suspected.
No evidence of carcinogenic effects has been reported. On the contrary, one would expect a decreased risk of endometrial and ovarian cancers based on experience with oral contraceptives. Although congenital anomalies have been reported in Norplant users, neither a causative relationship nor evidence of teratogenesis have been established. Finally, within 48 hours after removal of the implants, levonorgestrel is no longer detectable in the serum. Most women rapidly resume normal ovarian function. Sivin et al 19 have shown an 83% pregnancy rate at 1 year after removal. Thus, it appears that Norplant has no long-term effects on fertility.
Despite the high frequency of menstrual irregularity and other mild side effects, user satisfaction and continuation rates have been high. A review of the literature reveals that at the end of 1 year, 76–98% of the women continue the use of Norplant. 9 At 5 years, 33–78% of the starting number continue its use. In a recent 5-year study in the U.S., Sivin et al 10 found annual continuation rates to always be more than 80%. Several studies have shown that younger women (younger than age 25 yrs) have lower continuation rates than older women (older than age 35 yrs). 9,10 However, Polaneczky et al 20 demonstrated that adolescent mothers who initiated Norplant postpartum had an approximately 95% continuation rate at 1 year as compared with 33% of those who chose oral contraceptive pills. Furthermore, 74% reported that they were “very satisfied” with Norplant, and 95% would recommend it to others, as compared with 38% and 79% of oral contraceptive users, respectively. This pattern of use resulted in a low pregnancy rate in those who chose Norplant (one patient who discontinued Norplant, or 2%), as compared with a 38% pregnancy rate in those who initiated oral contraceptives.
The most common reason for discontinuation in the first year of use is menstrual irregularity, with the second most common reasons being headache and weight changes. In the latter years of use, desire of pregnancy becomes the most common reason. 10 Appropriate patient counseling helps to select the right candidates for the method and prevents the surprise of unwanted side effects. Several studies have shown that thorough and informative counseling before insertion resulted in the greatest satisfaction and continuation rates. 3 Tables 1 and 2 list the characteristics of appropriate candidates and contraindications to use, respectively. Because of lack of data, the manufacturer also lists warnings based on experience with combination oral contraceptive pills. These include hypertension, cerebrovascular disease, myocardial infarction, gallbladder disease, history of thromboembolism or coagulopathy, and smoking in women older than 35. Also, Norplant is probably not the best choice for women using drugs that accelerate hepatic microsomal metabolism, eg, phenobarbital, phenytoin, rifampin, and carbamazepine.
PUBLIC HEALTH CONCERNS
Ironically, some of Norplant’s most appealing characteristics have been suspected of leading to adverse public health consequences. It has been theorized that because of Norplant’s long efficacy, women may be less likely to return to health care providers for regular examinations, Papanicolaou (or Pap) smears, and sexually transmitted disease screening. 11 Furthermore, some have speculated that its high efficacy may lead to even lower condom use and thus to higher exposure to sexually transmitted diseases. These issues are of a particular concern in the adolescent population.
These concerns have been addressed by several recent studies. These studies have consistently shown that Norplant users exhibit similar rates of gynecologic follow-up as oral contraceptive pill users. 11,20 It appears that need for prescription of oral contraceptive did not alter women’s likelihood of return to the health care provider, and these women were much more likely to conceive an undesired pregnancy. These studies further found that Norplant use had no significant impact on sexual activity, the likelihood of condom use, or the incidence of sexually transmitted diseases. 3,11,20
ADVANTAGES AND DISADVANTAGES
The description of Norplant can perhaps be best concluded by emphasizing the method’s advantages and disadvantages. Its major advantage is high efficacy with no effort required from the user. The method is safe, with essentially no risk for serious complications. Norplant does not contain estrogen and therefore can be used by many women in whom combined oral contraceptives are contraindicated. Finally, its effect is limited to duration of use; once removed, fertility is rapidly restored, allowing for accurate family planning.
The main disadvantage is the high incidence of menstrual irregularity, which is not well tolerated by a minority of users. However, most women are not troubled by this side effect if appropriately counseled. Another disadvantage is the requirement of an office procedure for both initiation and termination of the method. This causes apprehension in a large proportion of women. In practice, however, most women tolerate insertion and removal without any difficulty. The occasional difficult removal may also provoke clinician anxiety and make the clinician less likely to recommend the method. Norplant’s high initial cost is also a disadvantage, but if used for several years, the cost is comparable to other methods. Other disadvantages include the side effects reported previously. Most of these are well tolerated, as evidenced by the high satisfaction rates of the method. The implants can be visible in thin women and this may be unacceptable to some. Finally, Norplant offers no protection from sexually transmitted diseases, but its use has been demonstrated to have no significant impact on sexuality or the use of condoms.
To address the previously mentioned concerns, researches have been developing various progestins and using alternative delivery systems. An ideal implant would preserve Norplant’s advantages while minimizing the disadvantages.
Norplant II is two-rod levonorgestrel system. Each implant is 4.4-cm long and is composed of a cured homogeneous mixture of the drug and a polydimethylsiloxane elastomer covered by silicone rubber tubing. 19 It is the only other implantable contraceptive approved by the FDA. Norplant II is approved for 3 years of use, but has been shown to be effective for up to 5 years.
Norplant II has been studied since the early 1980s with two different elastomers. 2 Because it uses two rods instead of six, both insertion and removal are faster and easier than Norplant. Studies have shown Norplant II to have release rates, pregnancy rates, and side effect profiles similar to those of Norplant. 2,19 The easier insertion and removal of this system is an obvious advantage over Norplant.
Implanon is a single-rod implant that is 4-cm long and 2-mm in diameter. It contains 68 mg of 3-keto-desogestrel (etonogestrel) in an ethylene vinyl acetate (EVA) copolymer core surrounded by an EVA membrane. 18 3-keto-desogestrel is a 19-nortestosterone derivative and the biologically active metabolite of desogestrel. Because desogestrel has been extensively studied in combination oral contraceptive pills, its safety profile has been established. 3-keto-desogestrel is significantly more potent than levonorgestrel; a serum concentration of only 0.09 ng/ml inhibits ovulation in most women. 2 Furthermore, because less 3-keto-desogestrel is required, a single implant is adequate. Serum concentrations of the progestin adequate for contraception have been shown to be present for 3 years or more in Implanon users.
More than a dozen clinical studies using Implanon have been performed, and zero pregnancies have been recorded in more than 4,000 woman-years of use. 18 Because the system consists of only one rod, insertion and removal are greatly simplified, with a mean time of 0.61 and 2.18 minutes, respectively. When compared with Norplant, the incidence of frequent and prolonged bleeding is lower, whereas the incidence of amenorrhea and oligomenorrhea are higher. 18 The incidence of other side effects such as weight gain, headache, and acne was low and similar to Norplant. Implanon was approved in the United Kingdom in 1999, and its approval by the FDA is presently expected. 5,21
Uniplant is also a single rod system but consists of 55 mg of nomegestrol acetate in a 3.5-cm long, 2.4-mm diameter, Silastic capsule. This system has been shown to provide highly effective contraception for up to 1 year. 8,15 Because Uniplant is a single implant, insertion and removal are again greatly simplified. However, the incidence and degree of menstrual irregularity have been shown to be similar to those of Norplant. Also like Norplant, user tolerance for these symptoms appears to be high. 15
An alternative approach to resolving the difficulties of implant removal is to eliminate the need for removal altogether. Capronor is a 40-mm rod containing levonorgestrel in an E-caprolactone polymer. The polymer releases the progestin 10-times faster than silastic and thereby one implant can achieve adequate serum concentrations. 2,21 Although the implant is biodegradable, it appears that it maintains its integrity for at least 1 year; removal is facilitated because a fibrous capsule does not form. Capronor has been shown to maintain serum concentrations similar to Norplant, ie, an average of 0.30 ng/ml, and its side effect profile is not surprisingly similar. 2 Clinical studies are currently in progress.
Another form of biodegradable implants is also currently undergoing investigation. These are pellets containing approximately 90% norethindrone and 10% cholesterol. They are expected to release norethindrone for 12 to 18 months and to dissolve within 2 years. 2,21 The number of pellets required for adequate serum levels remains to be determined, with studies showing that four pellets are likely to achieve anovulation and amenorrhea. Insertion of the pellets is reported to be simple; however, removal becomes impossible after several months. 2,21
Implantable contraception represents a safe, reversible form of long-term family planning with distinct advantages. It does not contain estrogen, thus avoiding many of it contraindications. Importantly, it is extremely effective, has high continuation rates, and is well tolerated. The main side effects of Norplant are irregular menstrual bleeding and the occasional difficult removal. Although recent high-profile litigation has severely diminished enthusiasm for Norplant, the FDA has reaffirmed its safety and efficacy. Norplant remains a viable family planning option for carefully selected women. New contraceptive implants may soon be available accentuating the advantages of Norplant while minimizing the disadvantages.
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