Irving Sivin

International experience with Norplant and Norplant-2 contraceptives.

Experience encompassing more than 20,000 woman-years of use of NORPLANT capsules and 6,000 woman-years of trials of NORPLANT-2 rods is reviewed. Implant contraception repeatedly has been associated with low pregnancy rates and high continuation rates through five full years of use. Weight has proved to be a factor related to effectiveness. Women weighing less than 50 kg experienced cumulative five-year pregnancy rates well below 1 per 100, whereas the overall cumulative rate has been 3.5 per 100. Medical events reported during use that have led to discontinuation are analyzed from four large data sets.

Health during prolonged use of levonorgestrel 20 μg/d and the Copper TCu 380Ag intrauterine contraceptive devices: a multicenter study * †

OBJECTIVES To measure and compare the incidence of adverse events during use of two medicated intrauterine devices (IUDs). DESIGN A multicenter prospective 7-year randomized study. SETTING Family planning clinics, primarily in developing countries. SUBJECTS Women age 18 to 38 years at admission, desiring contraception and without contraindications to IUDs. MAIN OUTCOME MEASURES Incidence of complaints, conditions, and rates of specific termination for each IUD. METHODS Subjects recorded menstrual events, and clinical staff registered all complaints and conditions found on examination at four first-year clinic visits and at semiannual visits thereafter. Difference in rates were analyzed by chi 2 statistics. RESULTS Annual pregnancy rates for each IUD averaged 0.2/100 women whereas upper genital tract infection occurred at rates of 0.6 to 0.7 per 100 years of use. The levonorgestrel-releasing IUD significantly decreased bleeding and spotting days in comparison with historical data for noncontraceptors and with the copper-medicated IUD. Dysmenorrhea, vaginitis, and myoma in women with the levonorgestrel IUD were markedly decreased in comparison with the experience of copper IUD users. Significantly higher rates of amenorrhea, delayed ovarian follicular atresia, skin and hair conditions, and headache were observed with the steroid IUD than with the copper-releasing IUD. Rates of reported adverse effects for either IUD were highest in the first 2 years of use and among women under age 25. CONCLUSIONS Long-term use of copper or levonorgestrel IUDs is characterized by very low rates of pregnancy and by a low and declining annual incidence of side effects, including pelvic infection and borderline anemia. The levonorgestrel-releasing IUD reduced the incidence of bleeding and, in the long term, of myoma and myoma-related surgery in comparison with the copper T IUD. Both IUDs proved highly acceptable and had few unanticipated side effects.

PROLONGED INTRAUTERINE CONTRACEPTION: A SEVEN-YEAR RANDOMIZED STUDY OF THE LEVONORGESTREL 20 mcg/DAY (LNg 20) AND THE COPPER T380 Ag IUDS

A levonorgestrel-releasing IUD and the Copper T 380Ag IUD were in randomized comparison for seven years in five clinics. In two other clinics the randomized study was truncated at five years, but use of the Copper T continued. No pregnancies occurred to users of either device in years 6 and 7. Cumulative pregnancy rates were 1.1 per 100 at seven years for the steroid-releasing and 1.4 per 100 for the copper-releasing IUDs. Cumulative rates of PID did not differ between devices. Infection rates appeared to be lowest during the sixth and seventh years of the study. Termination attributable to amenorrhea was the principal contributor to differences in cumulative continuation rates between devices. At the five clinics that carried the comparative study to seven years, cumulative continuation rates were 24.9 per 100 for LNg20 IUD users and 29.4 per 100 for TCu 380Ag users. Women who used either method for periods of five to seven years experienced, on average, marked to mild increases in hemoglobin as compared with levels at admission. The Copper T380 family and the LNg20 IUDs represent the most effective reversible contraceptive methods yet studied in long-term randomized trials.

Safety, efficacy, and acceptability of medical abortion in China, Cuba, and India: A comparative trial of mifepristone-misoprostol versus surgical abortion

OBJECTIVE We investigated safety, efficacy, and acceptability of an oral regimen of medical abortion compared with surgical abortion in three developing countries. STUDY DESIGN Women (n = 1373) with amenorrhea < or = 56 days chose either surgical abortion (as provided routinely) or 600 mg of mifepristone followed after 48 hours by 400 micrograms of misoprostol. This is the appropriate design for studying safety, efficacy, and acceptability among women selecting medical abortion over available surgical services. RESULTS The medical regimen had more side effects, particularly bleeding, than did surgical abortion but very few serious side effects. Failure rates for medical abortion, although low, exceeded those for surgical abortion: 8.6% versus 0.4% (China), 16.0% versus 4.0% (Cuba), and 5.2% versus 0% (India). Nearly half of failures among medical clients were not true drug failures, however, but surgical interventions not medically necessary (acceptability failures or misdiagnoses). Women were satisfied with either method, but more preferred medical abortion. CONCLUSION Medical abortion can be safe, efficacious, and acceptable in developing countries.

Long-term contraception with the levonorgestrel 20 mcg/day (LNg 20) and the Copper T 380Ag intrauterine devices: A five-year randomized study

An intrauterine device, releasing approximately 20 micrograms/day of levonorgestrel (LNg 20), used by 1124 women, was studied in a randomized trial of five years duration in comparison with the Copper T, model TCu 380Agm in 1121 women. At five years, the gross cumulative pregnancy rate of 1.1 +/- 0.5 per 100 among users of the LNg 20 devices was not significantly different from the rate of 1.4 +/- 0.4 per 100 experienced by users of the Copper T 380Ag. The steroid-releasing IUD had significantly higher termination rates for expulsion and amenorrhea, a significantly lower termination rate for other menstrual problems and pain, and a lower continuation rate. The five-year continuation rate among women using the TCu 380Ag was 40.6 per 100 as compared with that of 33.0 per 100 among women randomized to the LNg 20 device (P less than .001). Terminations attributed to amenorrhea with the LNg device primarily account for differences in continuation. These two intrauterine devices are the most effective long-term, reversible IUDs yet reported in the literature. No other contraceptive methods have exhibited such low long-term pregnancy rates in randomized comparative trials.

A five-year clinical trial of levonorgestrel silastic implants (Norplant™)

Abstract Silastic implants containing the progestin, levonorgestrel, were tested as a long-term contraceptive system in 101 women. During five full years of use, no pregnancies occurred. The 5-year continuation rate was 54%. Menstrual irregularities were the most frequent reason for termination of use but only during the first year. More than half of the terminations for this reason were in the first year. Some of the subjects elected to continue use of the implants beyond 5 years, allowing release rate data to be obtained through 6 years. From the second through the sixth year of use, the implants delivered a constant 30 micrograms per day of levonorgestrel to the subjects, and even after six years 57% of the original steroid content remained in the capsules. Return of fertility following removal was essentially immediate and not related to time of use. Medical reasons for removal were infrequent and no pattern was discernible.

Long-acting more effective Copper T IUDs: a summary of U.S. experience 1970-75

Use of medication in the form of copper wire coiled around the vertical shaft of an inert plastic carrier was a major innovation in IUD technology. The copper medication enabled the IUD to be small yet as effective as larger nonmedicated devices. Small size permitted the IUDs to be used by women who had never been pregnant. This initial advance was not accompanied by an important improvement in effectiveness. Neither the TCu 200 nor the Copper 7, the first two copper devices, showed substantially lower pregnancy rates in the United States (Tietze and Lewit, 1972; Jain, 1975) or in developing countries (Sivin, 1976). When copper wire devices were introduced, a key question was how long they would remain effective, since their effectiveness stems from the action of copper slowly dissolving in the uterine environment. After prolonged use, some of the copper coils are shed and thereby, in theory, the device becomes less effective. At first, two years of use was thought to be the limit, but as experience accrued the TCu 200 was found to remain effective for three years (Jain and Sivin, 1977), and both the TCu 200 and the Copper 7 have been approved by the US Food and Drug Administration for three full years of use. Data presented in this paper indicate that the TCu 200 provides effective protection against pregnancy for four full years of use. Efforts to increase effectiveness and extend duration of protection have led to the development of two improved Copper T devices. In the TCu 380A, collars or cylinders of copper have been placed on the horizontal arm of the T, each collar providing 30 mm2 of copper surface. These collars fit tightly onto the plastic and can be eroded from one side only. Erosion may pit the surface of the collars but cannot fragment them. Thus the copper in the collars will be available for contraceptive effect for many years. A theoretical advantage of placing collars on the horizontal arms of the T is that the copper supply is brought closer to the fundus of the uterus. Because implantation tends to occur high in the uterus, fundal placement of copper is considered to enhance effectiveness. In addition to the 60 mm2 of copper collars on the horizontal arms, the TCu 380A has 320 mm 2 of thick copper wire on the vertical shaft of the T, a surface area achieved by using more or tighter turns of wire than used in the TCu 200 device. A sixyear lifetime is the minimum duration of effective protection predicted for this device. This prediction is based on the assumption of slow fragmentation of the wire, leaving only the 60 mm2 of copper in the collars available for contraceptive effect after the wire has severely fragmented. In the second new device, the TCu 220C, collars of copper are placed on both the vertical and horizontal arms of the T form. Wire was eliminated entirely. With a total copper surface area of 220 mm2 in the form of collars, an effective lifetime for this device is estimated to be 1015 years, as no fragmentation is to be expected.

NORPLANT CONSENSUS STATEMENT AND BACKGROUND REVIEW

This review has highlighted the attributes of a very important new method of contraception. The signatories to this document agree that, with the provision of appropriate information and instruction for the user, Norplant is a good contraceptive choice to be made available worldwide in family planning programs that have the resources for appropriate training and counseling. The signatories to this document are acting in their own personal capacity and not as representatives of any particular organization.

Release rates of levonorgestrel from silasticR capsules, homogeneous rods and covered rods in humans

Three forms of subdermal implants containing levonorgestrel are described. These are: capsules, in which the powdered drug is sealed inside of lengths of Medical Grade Silastic tubing; homogeneous rods, in which the drug is uniformly dispersed in Silastic 382 Medical Grade Elastomer; and covered rods, in which a core rod of drug and filler-free polydimethylsiloxane polymer (50:50, Wt:Wt) are sealed inside thin-walled Silastic tubing. Long-term in vivo release rates from human subjects are presented; 6.5 years for capsules, 3.6 years for homogeneous rods and 4 years for covered rods. Sets of six capsules release a decreasing amount of drug through the first few hundred days in situ and after 500 days a fairly constant rate of about 35 micrograms per day is released (2 micrograms/cm). Homogeneous rods deliver a continuously declining amount of drug during the entire time studied. In the first 100 days the release averages 136 micrograms per day from a set of three 3-cm rods (15 micrograms/cm), gradually declining to 30 micrograms per day (3.3 micrograms/cm) from day 800 to day 1300. The covered rods deliver at a constant rate of 17.5 micrograms per day for a 3-cm rod (5.83 micrograms/cm) through 4 years.

Clinical assessment of treatments for prolonged bleeding in users of norplantR implants

The effectiveness of three drugs in controlling prolonged bleeding in the first year of NORPLANT implants use was tested. The drugs were levonorgestrel (L-Ng, 0.03 mg twice a day for 20 days), ethinylestradiol (EE, 0.05 mg per day for 20 days) and ibuprofen (Ib, 800 mg three times a day for 5 days) and were given orally. A control group received a placebo (PL, one pill of lactose for 20 days). Treatment should start each time a woman experienced eight consecutive days of bleeding or spotting. The 183 volunteers were not aware of the drug administered. A daily record of bleeding and spotting and of treatment intake was maintained. One-hundred-forty women completed the study period; 60 never used the prescribed treatment. Women treated with the three test drugs had significantly fewer bleeding and spotting days during the treated month and also throughout the study year than women using the placebo. The mean number of bleeding plus spotting days per actually treated subject in the first year was 77, 94, 101 and 129 days for the EE, Ib, L-Ng and PL groups, respectively. The administration of EE might help in the management of prolonged bleeding during the first year of NORPLANT implants use.