As the first real contraceptive innovation in over 20 years, and as a long-acting method requiring clinical intervention for insertion and removal, Norplant raised an especially wide range of issues. It also encountered a number of difficulties. In April 1997, an Institute of Medicine (IOM) workshop on implant contraceptives reviewed newly available data on Norplant's efficacy, safety, and use; considered lessons learned from the method's development, introduction, and market experience; and explored approaches based on those lessons that could improve the environment for contraceptive research and development and make market entry for new contraceptive technologies less troubled. In addition to presenting the IOM workshop findings, the present article calls attention to the rich scientific prospects available for development of the next generation of contraceptives, and notes signs of an evolving new paradigm, essential if those prospects are to be realized to any significant extent.

BACKGROUND

Women using progestogen-only contraceptives are commonly troubled by irregular bleeding. Endometrial vessel breakdown and repair is thought to be locally regulated under the indirect influence of sex steroids. Most information about endometrial vessels is derived from blind biopsies taken in an outpatient setting. Hysteroscopy allows in-vivo observation of the whole endometrial surface, including vessel morphology, distribution and areas of bleeding, as well as information about non-vascular structures that may not be accessible from biopsies.

METHODS

Hysteroscopies were performed on 34 women using the levonorgestrel contraceptive implant system (Norplant(TM)) and in a comparison group of 20 women complaining of menorrhagia due to ovulatory dysfunctional bleeding. The images were captured and vascular appearances assessed using image analysis.

RESULTS

The percentage of the superficial endometrium covered with blood vessels was found to be significantly greater in Norplant users compared with the comparison group (P = 0.0006). More superficial vessels were seen in those with recent frequent or prolonged bleeding and spotting (P < 0.0001). In Norplant users, but not in the comparison group, superficial vascular distribution was predominantly patchy (P < 0.0001). Unusual vascular appearances classified as 'neovascular' (P < 0.0001) and 'mosaic' (P < 0.0001) patterns were commonly seen in Norplant users but not in the comparison group. The hysteroscopic appearance of the endometrial epithelium, glands and stroma also differed between Norplant users and women with menorrhagia. Apparent shedding of the superficial endometrium was commonly seen by hysteroscopy in Norplant users during a bleeding episode (P < 0.0001). Prominent gland openings with thick mucus were commonly seen in Norplant users and small sessile polyps were seen in six cases.

CONCLUSIONS

These hysteroscopic observations provide further evidence that exposure to progestogens alters the superficial endometrial vasculature and may interfere with angiogenesis.

Estrogens and progestins are known to have profound effects on the immune system and may modulate the susceptibility to autoimmune diseases. A comprehensive literature search was carried out using PubMed for any of 153 autoimmune disease terms and the terms contraception, contraceptive, or their chemical components with limits of Humans + Title or Abstract. Over 1,800 titles were returned and scanned, 352 papers retrieved and reviewed in depth and an additional 70 papers retrieved from the bibliographies. Based on this review, substantial evidence exists linking the use of combined oral contraceptives to a lower incidence of hyperthyroidism, an increase in multiple sclerosis, ulcerative colitis, Crohn's disease, Systemic Lupus Erythematosus, and interstitial cystitis. Progesterone only contraceptives are linked to progesterone dermatitis and in one large developing world concurrent cohort study are associated with increases in arthropathies and related disorders, eczema and contact dermatitis, pruritis and related conditions, alopecia, acne, and urticaria. Hormonal contraceptives modulate the immune system and may influence the susceptibility to autoimmune diseases with significant increases in risk for several autoimmune diseases.

CONCLUSIONS

Hormonal contraceptives (HCs), such as the "pill," Norplant, and vaginal rings, are very potent hormones that have effects on the immune system, which is made up of white blood cells and lymph nodes and normally defends the body against invading bacteria, viruses and parasites. This review looked at the association of HC use to the development of autoimmune diseases, where the immune system turns against the body and causes damage to organs. There is good evidence that HC use is associated with an increased risk of several serious autoimmune diseases such as Crohn's disease (which causes inflammation of the bowels), Lupus (which causes inflammation in many organs), and interstitial cystitis (which causes inflammation in the bladder). Several other rarer autoimmune diseases are also linked to HC use. People contemplating the use of HCs should be informed of these risks.

This controlled cohort study aimed to evaluate the safety and efficacy of Norplant contraceptive implants in developing countries. Women initiating Norplant implants were index subjects and women initiating intrauterine devices (IUDs) or surgical sterilization were controls. Consenting participants at 32 clinics in eight developing countries were admitted and followed-up every 6 months for 5 years. Major and less serious health events during follow-up were recorded. Incidence rate ratios of health events adjusted for clinic were estimated for initial and current method use. This paper reports non-reproductive health events. The study involved 7,977 women initiating use of Norplant, 6,625 of IUD, and 1,419 of sterilization. Five years follow-up was completed for 94.6% of the women. The study accumulated 78,323 woman-years of observation. The initial method chosen accounted for 84.4% or more of observed woman-years in users of Norplant, IUD, or sterilization. Twenty-two of the recorded 34 deaths were due to accidents, suicide or homicide. Few deaths or major health events were due to cancer or acute cardiovascular diseases and were not associated with the contraceptive method used. The incidence rates of major health events were low and with two exceptions, there was no significant excess risk of serious morbidity for Norplant users compared with controls; among Norplant initiators gallbladder disease occurred at an incidence rate of 1.5 per 1,000 woman-years and was weakly associated with use of Norplant (rate ratio 1.52 [95% C.I. 1.02, 2.27]). For current Norplant users compared to controls, the rate ratio of a combined variable of hypertension and borderline hypertension was significantly elevated (1.81, [1.12, 2.92]). The occurrence of less serious health events was also low and several of them were significantly more often reported among Norplant users. Headache-migraine, weight gain, mood disturbances, pruritus, eczema, and acne had incidence rates among Norplant users of 11.5, 4.5, 2.8, 1.5, 1.4, and 0.9 per 1,000 woman-years, respectively, and were significantly higher than in controls. Respiratory health problems, nonspecific symptoms, and several ill-defined conditions were also significantly more often reported for Norplant users, but some of the excess incidence may be attributable to reporting and detection bias. The study confirms the safety with respect to serious disease of Norplant, IUDs, and sterilization.

Subdermal contraceptive implants involve the delivery of a steroid progestin from polymer capsules or rods placed under the skin. The hormone diffuses out slowly at a stable rate, providing contraceptive effectiveness for 1-5 years. The period of protection depends upon the specific progestin and the type of polymer. Advantages of progestin implants include long term contraceptive action without requiring the user's or provider's attention, low dose of highly effective contraception without the use of estrogen, and fertility is readily reversible after the removal of implants. The levonorgestrel implant Norplant R system is the only one that has been approved for distribution. The contraceptive efficacy of Norplant is the highest observed amongst the most effective methods with an annual pregnancy rate of 0.2 during the first and second year and 1.1 on the fifth year. Menstrual problems are the main reason for the discontinuation of Norplant and 9% of women stopped using it during the first year of treatment. Other implants are still under development trying to simplify the method by reducing the number of units and to introduce other progestins that may minimize side effects. Norplant-2 was designed to release the same dose of progestin from only two covered rods. Evaluation of 1400 women enrolled, indicates that over 2 years the cumulative pregnancy rate is below 0.5 per 100 women. There are three single implants under development: Nestorone, 3-Keto-desogestrel and Uniplant that are expected to be effective for 1-2 years. Phase II clinical trials with Nestorone have been completed and no pregnancies have been observed in 1570 woman-months of use. Bleeding irregularities occurred in 20-30% of the women but there were only four terminations because of bleeding problems. A multricentric study is ongoing with a newly designed 3-keto-desogestrel implant named Implanon, which releases approx. 60 micrograms/day of the hormone. The objectives of this study are to assess contraceptive efficacy, safety and acceptability of Implanon. Another multricentric study is ongoing with Uniplant, which releases nomegestrol acetate with a duration of action for only 1 year. The objectives of the trial are to study the endocrine profile of Uniplant users and to evaluate the efficacy and acceptability of the method.

NORPLANT progestogen-only implant contraception provides several years of effective protection against pregnancy following a single application. It is reversible whenever desired, with return to normal fertility. Drug release and concentrations are maximal in the first month of use, when a set of six capsules releases approximately 85 micrograms/day of levonorgestrel. Release is 25-30 micrograms/day at 60 months. Circulating drug concentrations and pregnancy rates vary inversely with body weight at placement, but even among heavier women, failure rates are below those of oral contraceptives in the general population. Side-effects are most marked at the initiation of use. Disruption of normal menstrual patterns occurs in 70-80% of recipients initially. Menstrual blood loss is decreased, however, and most women experience modest increases in haemoglobin. Headache, acne, other skin or hair problems, changes of weight and of mood and abdominal pain, are the most common side-effects attributed to NORPLANT contraception. The frequency of occurrence of side-effects diminishes with increased duration of use. The comparative paucity of major side-effects, coupled with the method's convenience and effectiveness and its very long action have made NORPLANT implants highly acceptable in both developing and developed countries.

Improperly placed Norplant implants pose a risk to neurovascular structures at the time of removal. Appropriate attention to insertion and removal should minimize the chance of injury. However, when injuries do occur, a logical and systematic approach to evaluation of the injury can help predict the outcome and establish a plan of care for the patient.

A total of 627 women who had discontinued the use of the Norplant-II implants for various reasons and were exposed to the risk of pregnancy were followed-up for two years for return of fertility. The cumulative conception rates in women who had discontinued due to planning pregnancy were 80.3 per 100 women at one year and 88.3 per 100 women at two years. The majority of women who did conceive (90 percent), had full-term normal live births; about 4 percent of women had spontaneous abortions, the remaining 6 percent decided on elective termination of pregnancy (ETP). The cumulative conception rates in women who discontinued due to bleeding irregularities and 'other reasons' were 64.5 and 55.8 per 100 women at one year and 77.9 and 75.1 per 100 women at two years, respectively. These rates were significantly lower as compared to those observed in women who discontinued due to planning pregnancy. A large proportion, about 40 percent, of women who conceived after discontinuation of the method due to bleeding irregularities and "other reasons," opted for ETP indicating that many women in these two groups did not desire another child and that such women need to be counselled for adopting another method of contraception. The spontaneous abortion rates observed in ex-users of Norplant-II implants (1.7 to 4.4% pregnancies) were comparable to the spontaneous abortion rates prior to Norplant-II implant use (3.6% pregnancies) indicating that ex-users of Norplant-II implants were not at a higher risk of spontaneous abortion.(ABSTRACT TRUNCATED AT 250 WORDS)

The safety and efficacy of four contraceptive implants, plant, Implanon, Nestorone and Elcometrine, have been evaluated during use in the postpartum period by lactating women. These implants provide highly effective contraceptive protection with no negative effect on breastfeeding or infant growth and development. Breastfeeding women initiating Norplant use in the second postpartum month experience significantly longer periods of amenorrhea than do untreated women or intrauterine device users. After weaning, the bleeding pattern is similar to that observed in non-nursing women. Norplant use does not affect bone turnover and density during lactation. Norplant and Implanon release orally active progestins while Nestorone and Elcometrine implants release an orally inactive progestin, which represents an advantage since the infant should be free of steroidal effects. The infant's daily intake of steroids (estimated from concentrations in maternal milk during the first month of use) range from 90 to 100 ng of levonorgestrel (Norplant), 75-120 ng of etonogestrel (Implanon), and 50 ng and 110 ng of Nestorone (Nestorone and Elcometrine implants, respectively). Nursing women needing contraception may use progestin-only implants when nonhormonal methods are not available or acceptable. Implants that deliver orally active steroids should only be used after 6 weeks postpartum to avoid transferring of steroids to the newborn.

At Klinik Raden Saleh, Department of Obstetrics and Gynaecology, University of Indonesia, from 1 May until 31 August, 1981, Norplant contraceptive implants were inserted into 437 Indonesian women. The continuation rates of Norplant at first, second, third, fourth and fifth year were, respectively, 96%, 92%, 88%, 82% and 78%. Bleeding problems were the most common cause for removal. The cumulative five-year net pregnancy rate for Norplant was 1.8 per 100 women. The Norplant contraceptive system is thus seen to combine the highest acceptability as measured by its continuation rate with the highest long-term effectiveness among the available temporary contraceptive methods.

OBJECTIVE

To determine whether initiation of on-site dispensing of hormonal contraceptives (oral contraceptive pill, Depo-provera, and Norplant) in six urban school-based health centers reduced time to initial selection, and increased their consistent use among sexually active females.

METHODS

Participants were sexually active females who received family planning care in a school year before (1994-1995 cohort) or after (1996-1997 cohort) the initiation of on-site dispensing. Data on contraception and sexual behavior were collected at each family planning visit. Cohorts were compared using Student's t-tests and Chi-square tests, analysis of covariance, and logistic regression.

RESULTS

About 59% of the 1994-1995 cohort selected hormonal contraceptives at the first or second visit; this increased to 72% of the 1996-1997 cohort (chi(2) = 11.3; p <.001). After adjustment for cohort differences, the 1996-1997 cohort consistently selected hormonal contraceptives a longer period of time, although the difference did not reach statistical significance (adjusted means: 1994-1995 cohort = 73 days, 1996-1997 cohort = 81 days; t = 1.6, p <.10).

CONCLUSIONS

Sexually active females receiving family planning care select methods of hormonal contraception sooner and somewhat more consistently when the clinics in their high schools can dispense contraceptives on-site.

OBJECTIVE

The study aimed to assess the possible differences in effects of Implanon and Norplant implants on liver function over 2 years of use.

METHODS

This is a 2-year open randomized study of 80 implant (Implanon and Norplant) acceptors. Selected parameters of liver function were tested in the serum before implant insertion and at 6, 12 and 24 months after implant insertion.

RESULTS

In both the implant groups, the mean total and unconjugated bilirubin and the gamma-glutaryl transferase levels were significantly raised during implant use. For none of the subjects, at any sampling period, did the levels exceed the normal range in our population. There was no significant elevation of any other liver enzymes in either group.

CONCLUSIONS

It appears that there may be mild hepatocellular dysfunction associated with the use of both Implanon and Norplant, which is possibly of no clinical significance to the healthy acceptor.

This study reports on a simple, feasible and easily learned technique for Norplant implants removal. This technique is modified from the needle elevation technique. The objective of this study was to introduce an alternative Norplant implants removal technique, especially for misplaced capsules. Fifteen Norplant implants clients whose capsules were difficult to palpate had removal by this technique. The mean duration of Norplant implants use was 18.4 +/- 12.5 months. The mean length of removal time was 10.4 +/- 4.5 minutes. None of the capsules was damaged during the removal. No immediate or late complications were observed. The conclusion is that the modified needle elevation technique is a simple and easy method of removing misplaced Norplant capsules with less complications.

Following adverse widespread publicity in the United Kingdom and the United States, it is commonly believed that discontinuation rates for the contraceptive implants Norplant in the UK are high. We have compared discontinuation rates between new intrauterine device (IUD) users (253 women) and new Norplant implant users (502 women) over 33 months following the introduction of Norplant implants among a population of women attending the same clinic and counseled in the same manner by the same group of providers. Women choosing the IUD were slightly older and were more likely to be changing their contraceptive method because of dissatisfaction with their current method. Nor plant implant users were more likely to have completed their families. Continuation rates for Norplant implants were significantly higher than for IUD at 12, 18, and 24 months after insertion. At 24 months, continuation rates for Norplant implants were 72% compared with rates of 55% for IUD users. Higher continuation rates may be related more to factors associated with the providers than with the users of these two long-acting methods.

A five-year study of NORPLANT II rod implants was undertaken in four large cities and metropolitan areas in eastern China. Designed to test the safety, efficacy and acceptability of these implants, the study involved 1,208 women and was conducted concurrently with a similar study of NORPLANT capsule implants. At the end of five years, the gross pregnancy rate was 0.65 per 100, and the continuation rate was 65.3 per 100. Both these values were similar to and not statistically different from the rates of the capsule implant users. In 4,828 woman-years of use, there were few severe adverse events reported. Users and providers found the method to be an acceptable long-term contraceptive method of great reliability.

A longitudinal study of coagulation parameters was carried out on 47 women using the levonorgestrel subdermal implants, NORPLANT. The study comprised measurement of platelet count, prothrombin time, thrombin time, partial thromboplastin time with kaolin, clotting factors I, II, V and VI through XIII, plasminogen, antithrombin III (AT III), alpha 1 antitrypsin, alpha 2 macroglobulin and fibrinogen degradation products. The tests were done at admission and after one, three and six months of NORPLANT use. Parallel and similar studies were done on two groups of oral contraceptive users; the first group used a pill containing 1 mg norethisterone and 50 micrograms mestranol, and the second a pill consisting of 150 micrograms levonorgestrel and 30 micrograms ethinylestradiol. Results from this ongoing study have indicated that women using NORPLANT implants evidenced lack of effects on most of the parameters tested except for factor VII activity which was increased and AT III concentration which was decreased after six months of use. The combined pill users evidenced marked changes in the platelet count, the screening tests and in most of the coagulation-promoting factors; the changes were apparent after three months of use and became more pronounced after six months. The results demonstrate, with marked contrast, that the implants had less pronounced effects on the blood coagulation system than did the combined pills used in this study.

David Bromham's editorial on contraceptive implants ignores the wider issues to voice concern that trial by media could limit contraceptive choice by jeopardising research into new methods. However, it is more beneficial to the public for points of conflict to be debated openly. Furthermore, the impetus for research into new contraceptive technology is driven by profit and political motives and is only marginally affected by the media. Implanted contraceptives may increase the choice of contraceptive methods, but they put control of fertility increasingly into the hands of the medical profession. Herein lies their greatest problem: their potential to increase providers' control over clients' choice. There is the danger that certain groups of women may be targeted for their use: in the United States the coercive use of Norplant for mothers receiving welfare benefit has been suggested. Long acting contraceptives are a contraceptive of choice only when they are available without pressure, as part of a wider menu; when instant removal on request is guaranteed; and when there is an open and free flow of information and opinions between users, health professionals, and special interest groups.

The study compares NORPLANT subdermal implants acceptors enrolled randomly for two different insertion procedures. One group (420 women) received the implants with the use of a scalpel according to the manufacturer's instructions. The other group (423 women) received the implant without an incision, directly through a sharpened trocar. The local signs and symptoms were observed at 7 and 30 days after insertion. Pain, tenderness, edema/swelling, ecchymosis and defective scar were considered. Complication rates were low and no significant differences were found between the two procedures. Based on the data of this study, we recommend inserting NORPLANT implants without the use of a scalpel.

This study describes the effects of Norplant on haemostatic function after 5 years of use in 97 women. There was a decrease in vitamin-K dependent Factors II, V, VII and reduction in fibrinolytic activity at 2 and 4 years of use. Increased platelet numbers and accelerated platelet aggregation were found throughout the 5 years of Norplant use, whilst raised alpha 2-Macroglobulin (a2-M) and antithrombin III (ATIII) antigen level were observed for up to 4 years of use. Prolonged Norplant use does not appear to activate the coagulation system and does not enhance a state of hypercoagulation.

OBJECTIVE

Our purpose was to describe the techniques we have developed to remove nonpalpable subcutaneous and intramuscular Norplant capsules with the patient under local anesthesia and with use of real-time ultrasonographic guidance in an office setting.

METHODS

This was a noncomparative, descriptive study of our experiences with 27 women with 64 deep Norplant capsules.

RESULTS

Twenty-four women had all their nonpalpable and intramuscular implants removed under real-time ultrasonographic guidance with no complications. One woman was not a candidate, one was lost to follow-up, and another elected to retain her last implant.

CONCLUSIONS

Real-time ultrasonographically guided procedures can be performed with the patient under local anesthesia in an office setting and can reduce the number of operative procedures necessary to remove nonpalpable and intramuscular Norplant capsules.

OBJECTIVE

This study develops a clinical profile of urban teens who selected Norplant for contraception; determines which variables identify the subjects most likely to be compliant with the method; and determines the most common reasons for early termination of use.

METHODS

Demographic and health history data and reasons for termination of use were collected prospectively for 122 inner city teens who received Norplant. Life table analysis and the Mantel-Haenszel procedure were used to investigate differences between Norplant retainers and terminators.

RESULTS

The sample consisted of black and Hispanic teens between the ages of 13-19 years, the majority of whom had one or more children and were in school. One and two year retention rates were 71% and 62%. The highest removal rates occurred during the 3-6 month interval after insertion. A significant finding was that teens who have experienced induced abortion were more likely to retain Norplant. Common reasons for termination of use included general and social concerns, including pregnancy desire.

CONCLUSIONS

Norplant retention rates for this teen sample were greater than the compliance rates reported for other conventional methods. Similar to noncompliance with oral contraceptives, discontinuance of the method was most likely to occur in the first 6 months of use. A history of induced abortion identifies those teens most likely to retain Norplant, suggesting that these teens might evaluate contraceptive risks and benefits differently than those with no abortion history. Pregnancy desire was a common reason for terminating Norplant use.

A comparison of the relative costs of the injectable contraceptive (depot medroxyprogesterone acetate) and the hormonal implant (Norplant) indicates that the implant is a less costly contraceptive option when it is used for its full five-year lifespan. Over a five-year period, the implant costs $107 annually, compared with $140 per year for the injectable. However, if a woman discontinues the implant before she has used it for at least four years, the injectable becomes the less costly option. Relatively high continuation rates--around 95% annually--are necessary to make the implant the more cost-effective contraceptive method.