Prolonged effectiveness of Norplant(R) capsule implants: a 7-year study.

Soft tubing Norplant(R) contraceptive implants were studied in 1210 women for 7 years to measure the duration of effectiveness and the magnitude of the pregnancy rates over that time. Mean age at enrollment was 27.4 years. Of the enrollees, 42% were US residents. One-sixth (16.1%) weighed >/=70 kg at the time of implant placement. At the end of 5 years, the cumulative pregnancy rate was 1.1/100; at the end of 7 years, it was 1.9/100. No pregnancies occurred to any of the 400 women who enrolled in the study at age >/=30 years and who weighed <100 kg. Among women aged 18-33 years, the 7-year Norplant pregnancy rates are comparable to the median pregnancy rates of tubal sterilization methods for women of the same age and duration of use. For women aged >/=34 years, without regard to weight at admission, the 7-year effectiveness of soft tubing Norplant equals or surpasses that of tubal sterilization. For continuing implant users, annual pregnancy rates <1.0/100 in years 6 and 7, together with low cumulative pregnancy rates, testify that Norplant capsule implants remain highly effective for 7 years.

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.

PIP: The Norplant contraceptive implant has been registered in 60 countries and used by over 6 million women worldwide. Clinical studies have repeatedly confirmed this method's long-term efficacy and safety when used appropriately. Preliminary findings of the Post-Marketing Surveillance study of Norplant, a 5-year prospective study conducted in 32 family planning clinics in 8 developing countries in 1987-97, indicate an intrauterine pregnancy rate of 0.23/100 woman-years, an ectopic pregnancy rate of 0.03/100 woman-years, and a 67.3% continuation rate at 5 years. No significant excess of malignant neoplastic or cardiovascular disease has been observed. The major side effect is an irregular pattern of uterine bleeding, associated with about 25% of the discontinuations after 5 years of use. The quality of the family planning service is a major determinant of successful Norplant use and the degree of user satisfaction. Informed choice, the quality of follow-up care, easy access to removal services, and provider skills and attitudes are also critical. The signatories to this Consensus Statement (acting as individuals rather than representatives of their organizations) agree that, with the provision of appropriate information to users, Norplant is a good contraceptive choice that should be made available globally in all family planning programs with resources for appropriate training and counseling.

The performance of levonorgestrel rod and Norplant contraceptive implants: a 5 year randomized study.

A new contraceptive (LNG rod implants, Jadelle, Leiras Oy's registered trademark for rod implants) was prospectively evaluated in randomized 5 year comparison with Norplant (Population Council's registered trademark for contraceptive implants releasing levonorgestrel) capsule implants. The study involved 1198 women at seven centres. No pregnancies occurred in the first 4 years. At 5 years, the cumulative pregnancy rate was 1 per 100 users or less for each regimen. Annual discontinuation rates averaged 11-12 per 100 users (P > 0.05), corresponding to 5 year continuation rates of 55.1 for rods and 53.0 per 100 for capsules. Mean annual discontinuation rates for menstrual disturbances were 3.5 and 4.2 per 100 for rod and capsule implants respectively (P > 0.05), and mean annual removal rates for medical problems were 3.5 and 3.0 per 100 (P > 0.05) respectively. Apart from menstrual problems, headache, weight gain and acne were the principal medical reasons for removal. In proportional hazard analyses, family formation variables, age, parity and desire/non desire for another child, recorded at admission, significantly affected discontinuation rates for major decrement categories and for all reasons combined. Mean rod removal time was half that of Norplant (P < 0.01); complications of rod removal were at a lower rate. With these contraceptives indistinguishable in performance except for ease and speed of removal, LNG rod implants appear to be preferable to Norplant for use through 5 years by virtue of relative ease of removal.

PIP: This paper presents the 5-year randomized study on the performance of levonorgestrel rod (LNG) and Norplant contraceptive implants in 1198 women in 7 centers. In the first 4 years, no pregnancies occurred. At 5 years, the cumulative pregnancy rate was 1/100 users or less for each regimen. Annual discontinuation rates averaged 11-12/100 users, corresponding to a 5-year continuation rate of 55.1/100 for rods and 53.0/100 for capsules. Mean annual discontinuation rates for menstrual disturbances were 3.5/100 for rod and 4.2/100 for capsule implants. Reasons for discontinuation of use were vaginal spotting or bleeding, irregular bleeding, headache, weight gain and acne. Proportional hazard regression models established that family formation variables, age, parity, and desire for another child, recorded at admission, significantly affected discontinuation rates for major decrement categories and for all reasons combined. Mean rod removal time was half that of Norplant. Complications of rod removal were at a lower rate. This study concludes that there is an extremely high contraceptive effectiveness for LNG rod and Norplant implants; however, LNG rod implants were more preferable than Norplant for its relative ease in removal.

Clinical performance of a new two-rod levonorgestrel contraceptive implant: a three-year randomized study with Norplant implants as controls.

In a randomized three-year clinical trial at seven clinics, the performance of levonorgestrel rod (LNG ROD) implants used by 600 women was compared with that of soft tubing NORPLANT implants used by 598 women. No pregnancies occurred in either group of women and, accordingly, body weight did not affect the efficacy of either type of implant. There were neither statistically significant nor important differences in termination rates for any reason over the three years. Complaint and illness rates during use of either of the two implant types were statistically indistinguishable and were attributable to the same set of conditions. Seventy-one per 100 of the women using each implant regimen continued to the three-year point, for an average annual continuation rate of 89 per 100. Removals of LNG ROD implants were accomplished in about half the time required for removal of Norplant capsule implants (p < 0.001).

Vaginal progesterone after tubal pregnancy.

We studied the effect of vaginal progesterone (P) treatment during the luteal phase of patients who had had a tubal pregnancy (TP) and were planning another, in a prospective, randomized, double-blind trial. The outpatient clinics of two University hospitals and three central hospitals had 135 patients treated for tubal pregnancy: 100 with grossly normal fallopian tubes (supposing an accidentally abnormal luteal phase as a possible etiology of their first TP) and 35 with signs of earlier pelvic inflammatory disease (PID etiology). They were treated with vaginal P (25 mg b.i.d.) or placebo during cycle days 16-24, for 10 months. Serum P levels after a single vaginal or oral dose were compared. The rates of conception, delivery, spontaneous abortion and recurrent TP were recorded, and fetal and placental weight measured. Both vaginal and oral formulas of P provoked a physiological (24-43 nmol/l) rise in serum concentrations. P and placebo-treated cycles resulted in a nearly equal number of pregnancies (33/37 resp.). Of the 55 infants born 53 were to mothers without signs of earlier PID (53/100); only 2 (2/35) to mothers in whom signs had been present. Recurrent TP occurred in 9% of all pregnancies. Four out of six recurrent TPs were patients with signs of PID (4/35), but two were without such signs (2/100): one occurred during placebo and one during P-treated cycle. Prophylactic P treatment of patients at risk of recurrent TP does not improve fertility or prevent recurrent TP. This indicates, that the functional etiology of recurrent TP, as compared to infection, is not important.

Rates and outcomes of planned pregnancy after use of Norplant capsules, Norplant II rods, or levonorgestrel-releasing or copper TCu 380Ag intrauterine contraceptive devices.

OBJECTIVES: The objectives were to measure rates of planned pregnancy and factors affecting these rates after use of very-long-acting contraceptive methods (Norplant or Norplant II implants, a levonorgestrel-releasing intrauterine contraceptive device, or the copper T (model TCu 380Ag) intrauterine contraceptive device. STUDY DESIGN: The design was a concurrent, multicenter prospective study of 372 women who stopped contraception for planned pregnancy. Analysis was by life-table, log-rank, and standard chi 2 methods. RESULTS: Pregnancy rates 12 and 24 months after cessation of contraceptive use were 82 and 89 per 100, respectively. Age at removal and family planning intentions at initiation of contraception were both significantly correlated with pregnancy rates (p less than 0.05), but former contraceptive regimen and duration of contraceptive use were not. Pregnancy outcomes did not deviate from normal limits and did not differ by contraceptive formerly used. CONCLUSION: Contraceptive implants releasing 30 micrograms/day of levonorgestrel or intrauterine contraceptive devices releasing 20 micrograms/day of levonorgestrel or having copper surface areas of 380 mm2 are associated with normal fertility after use for women seeking pregnancy at termination. Durations of use do not affect pregnancy rates.

PIP: A Norplant capsule releasing 30 mcg/day of levonorgestrel (LNG), Norplant II rods releasing 30 mcg/day LNG, an IUD releasing 20 mcg/day LNG, and a model TCu 380Ag model copper T IUD were used in trials by 2748 women at 7 centers during 1882-90. 372 women requested removal by the end of 1990. 10-12% of implant subjects and 17-20% years and mean parity was 1.75. The 12-month life-table rate of pregnancy was 82/100 for those planning pregnancy. 2 years later the rate was 89/100 achieved for in the first years before age 30; and 93/100 of younger women got pregnant 2 years after removal. Duration of use for or= 3 years resulted in a pregnancy rate of 84/100, while use 3 years yielded 81/100. The rates were 85/100 at 1 year and 92/100 at 2 years for women desiring more children compared with the 70 and 81/100 rate of family limiters. Age was a major factor: under 30 years with or= 37 months of contraceptive use the pregnancy rate was 93/100, while age or= 30 years and use of 37 months produced a rate of 58/100 at 1 year. 58% of former users of Norplant II rods, 34% of LNG-releasing IUD users. 43% of copper T IUD, and 37% of Norplant capsules became pregnant within 3 months. Amenorrhea of 90 days occurred in LNG IUD users at removal with 1st month pregnancy of 5/100, but the conception rate reached 80- 92/100 at 1 year. 88% of pregnancies ended with live births: 2 newborns with weight of 2500 gm and tubal pregnancy in a former Norplant II rod user. Female neonates made up 50.5% of births. The recovery of fertility outcomes were not adversely affected by these methods.

Transdermal oestrogen replacement therapy in a Finnish population.

In an open, multicentre study, transdermal administration of oestradiol (E2) by means of skin patches was investigated in a Finnish patient population suffering from typical post-menopausal symptoms. A total of 249 women applied a patch twice weekly for 6 months. Whereas 85% of the subjects were experiencing hot flushes and 83.5% sweating before therapy, only 5.7% and 11.8%, respectively, reported these symptoms at the end of the trial. Furthermore, 97.6%, 95.7% and 94.8% of the subjects reported that depression, headache and sleep disturbances, respectively, had disappeared during therapy. Skin irritation occurred in 18.2% of these predominantly fair-skinned women. Frequent sauna bathing did not interfere with the patch therapy. General acceptance of the treatment was excellent, 84.8% of the patients completing the treatment, of whom 78% were willing to continue the treatment after the trial. These results show that transdermal administration of E2 is effective in relieving post-menopausal symptoms. Local tolerability was good and the majority of the patients considered the transdermal treatment to be superior to their previous oral replacement therapy.

Effective contraception with the levonorgestrel-releasing intrauterine device: 12-month report of a European multicenter study.

The use-effectiveness of an intrauterine contraceptive device releasing 20 mcg of levonorgestrel daily (Lng-IUD), and of a Nova T copper-releasing IUD, were studied in a randomized, comparative multicenter trial. The Lng-IUD was inserted in 1821, and the Nova T in 937 women. The 12-month net pregnancy rate with the Lng-IUD (0.1 per hundred women) was significantly lower than that with the Nova T (0.9 per hundred). Removal rates for menstrual problems and/or pain were similar for the two methods (net rates 7.5 and 8.7, respectively). The 12-month continuation rates were 82.2 for the Nova T and 79.7 for the Lng-IUD. The reduction of the bleeding led to oligomenorrhea and amenorrhea in users of the Lng-IUD; the removal rate for these reasons was 1.4. The removal rate for hormonal side effects with the Lng-IUD was 2.4. Blood hemoglobin concentrations increased among users of the Lng-IUD and decreased among users of the Nova T. The results show that the Lng-IUD was a highly effective contraceptive method which reduced menstrual bleeding. It is a promising alternative for women desiring a highly effective method for long-term use.

PIP: The use-effectiveness of an intrauterine contraceptive device releasing 20 mcg of levon ISZ orgestrel daily (Lng-IUD), and of a Nova T copper-releasing IUD, were studied in a randomized comparative mulicenter trial. The Lng-IUD was inserted in 1821, and the Nova T in 937 women. The 12-month net pregnancy rate with the Lng-IUD (0.1/100 women) was significantly lower than that with the Nova T (0.9/100). Removal rates for menstrual problems and/or pain were similar for the 2 methods (net rates 7.5 and 8.7 respectively). The 12-moth continuation rates were 82.2 for the Nova T and 79.7 for the Lng-IUD. The reduction of the bleeding led to oligomenorrhea and amenorrhea in users of the Lng-IUD; the removal rate for these reasons was 1.4. The removal rate for hormonal side effects with the Lng-IUD was 2.4. Blood hemoglobin concentrations increased among users of the Lng-IUD and decreased among users of the Nova T. The results show that the Lng-IUD was highly effective contraceptive method which reduced menstrual bleeding. It it a promising alternative for women desiring a highly-effective method for long-term use.

[Subcutaneous hormone capsules]. / Ihonalaiset hormonikapselit.

PIP: Contraceptive implants containing progestin have been marketed in Finland since 1984. The method utilizes 6 silicon capsules of 36 mg levonorgestrel that are implanted inside the upper arm under local anesthesia. Each capsule is 34 mm long and 2.5 mm wide. The capsules release 100 mcg levonorgestrel a day during the 1st 3 months, after which dosage decreases to a level of 30-35 mcg a day within 15 months. The rate of release remains the same for a period of up to 6.5 years. Some users experience no ovulation or an incomplete luteal phase. The level of estradiol varies, although FSH, LH and androgen levels do no essentially change. Cholesterol ratios remain unchanged, but the levels decrease somewhat. Blood coagulation problems due to menstrual problems, primarily frequent, irregular bleeding and spotting. Side effects such as headaches, weight gain, mood changes can be caused by the capsule, as well as the contraceptive pill. During implantation and removal there is a small (0.3) risk of infection. Teratogenic and mutagenic effects are unlikely. Studies have shown no pregnancies occurring in the 1st 2 years of use. The 3rd year, the cumulative rate has been shown to be 0.3, and for the 4th year 0.7. To a great extent, contraceptive implants are utilized by women who have had bad experiences with other methods, and who already have the desired number of children. This method offers much promise to those women in developing countries, and has been proven to be well tolerated there.^ieng

Cholesterol and HDL-cholesterol values in women during use of subdermal implants releasing levonorgestrel.

Plasma concentrations of cholesterol, HDL-cholesterol, and levonorgestrel were determined in two groups of women using levonorgestrel-releasing subdermal implants. One group used six capsules (NORPLANT)*; the other six covered rods. Plasma concentrations of levonorgestrel among NORPLANT users averaged 700 pg/ml in the first two weeks of use, decreased to 300 pg/ml at 8 weeks, and to about 230 pg/ml by 50 weeks. Concentrations among covered rod users were 1.4 to 1.7 times higher at comparable time periods. Total serum cholesterol and HDL-cholesterol were decreased as compared with controls at all sampling intervals during the 114 weeks of the trial, although the differences did not meet tests of significance at all time periods. Decreases during the test period were of the order of 10 percent, except for total cholesterol among covered rod users where the decrease was less. Cholesterol to HDL-cholesterol ratios did not differ significantly from control values at any sampling period.

Contraception with long-acting subdermal implants. A five-year clinical trial with Silastic covered rod implants containing levonorgestrel. The International Committee for Contraception Research (ICCR) of the Population Council.

A total of 189 women volunteered to accept subdermal implants for contraception. The implants were "covered rods", consisting of a core rod containing equal parts by weight of levonorgestrel and polydimethylsiloxane and sealed inside a thin-walled tube of Silastic tubing with medical adhesive. In one study 78 women used 4 3cm rods (study 07) and in the other 111 women used 6 3cm rods. In 5 years of use there were no pregnancies in either group. Terminations because of menstrual problems were twice as frequent among the 4-rod users than among users of the 6 rods. Menstrual pattern analysis is presented for the two rod regimens and compared with the previously reported patterns for the 6-capsule regimen (NORPLANT). Long--term in vivo release rates are also presented.

Long-term experience with Norplant contraceptive implants in Finland.

Silastic implants containing the progestin, levonorgestrel, were tested as a long-term contraceptive system in 124 women. During five years of use no accidental pregnancy occurred. The first year continuation rate was 90% and the five-year continuation rate was 54%, including terminations for wish to become pregnant. The medically relevant continuation rate was 68% after five years. Menstrual irregularities were the most frequent reason for termination, but only in the first two years. 70% of the terminations for that reason occurred during the first two years. Terminations for other steroid-related reasons were infrequent. The follow-up will continue up to the end of the seventh year. Seven of seventeen women who requested removal of the implants because they wanted to become pregnant conceived during the first two cycles and only three were not pregnant one year after removal.

Long-term experience with Norplant implants in international clinical trials.

Norplant subdermal implants containing levonorgestrel were used for contraception and compared with the Copper T, Model T Cu 200, during 42 months of use in an open study in Chile, the Dominican Republic, and Finland. Among 324 women enrolled for the implant regimen, there were no pregnancies in the 1st 2.5 years, and 2 by the end of 42 months. 1st segment net and gross cumulative pregnancy rates were 0.7 and 1.2/100 respectively, at 3.5 years. Cumulative pregnancy rates for the T Cu 200 group were 2.9, net and 3.5/100, gross at 42 months. More than 1/2 of the implant acceptors, 51.6/100 were continuing use at 3.5 years, somewhat above the continuation rate of the T Cu acceptors, 43.5/100, but not significantly so.

Serum lipids and proteins during treatment with a new oral contraceptive combination containing desogestrel.

The present study was carried out to measure lipid and protein levels in serum of healthy women during treatment with a new oral contraceptive combination containing 0.075 mg desogestrel (Org 2969, 17 alpha-ethinyl-18-methyl-11-methylene-4-estren-17-ol) plus 0.050 mg ethinyloestradiol per tablet. All 30 volunteers took 1 tablet daily for 21 consecutive days, followed by a tablet-free period of 7 days. Treatment lasted 3 months. At the end of treatment serum total cholesterol had increased by 0.26 mmol/l (5.0%), high-density lipoprotein-cholesterol by 0.22 mmol/l (15.2%) and triglycerides by 0.43 mmol/l (50%); the calculated low-density lipoprotein cholesterol had decreased by 0.16 mmol/l (4.9%). All lipid concentrations had returned to initial levels 2 months after treatment stopped. After 3 months treatment serum ceruloplasmin, cortisol-binding globulin capacity, sex-hormone-binding globulin capacity and thyroxine-binding globulin had significantly increased by 85.2, 133, 206 and 101%, respectively. All protein levels returned to normal 2 months after treatment stopped. The relationship between serum lipids and hormone-binding proteins has been discussed, as well as the significance of the high-density lipoprotein level with regard to contraceptive treatment.

Three-year experience with NORPLANT subdermal contraception.

NORPLANTTM (Laboratorios Gutfol, S.A., Mexico City, Mexico) subdermal implants containing levonorgestrel were accepted by 816 women in a two-phase study initiated in 1975 and augmented in 1978. Through 3 years of first-segment use, acceptors experienced five pregnancies, a cumulative net rate of 0.7 per 100, and a gross pregnancy rate of 1.1 per 100. First-segment continuation at 3 years was at the rate of 44.6 per 100, an annual average of 76 per 100. NORPLANT users experienced irregular menstruation, with high interindividual variation, but with normal average numbers of bleeding days and of bleeding episodes. Hemoglobin levels increased moderately during implant use. The incidence of systolic blood pressure readings above 145 mm Hg or diastolic readings above 95 mm Hg was similar to that observed among users of the TCu 200 intrauterine device enrolled under the same selection criteria in the same clinics between the two phases of the NORPLANT study. Comparative data on pregnancy and other rates are also given for these intrauterine device acceptors.

Effects of oral contraceptive combinations containing levonorgestrel or desogestrel on serum proteins and androgen binding.

The effects of the oral contraceptive combinations 0.125 mg Org 2969 (desogestrel) (13-ethyl-11-methylene-18,19-dinor-17alpha-pregn-4-en-20-yn-17-ol) + 0.05 mg ethinyloestradiol (EE) and 0.125 mg levonorgestrel + 0.05 mg EE on serum sex-hormone-binding globulin (SHBG), ceruloplasmin, transcortin and ratio free testosterone over total testosterone (percentage free testosterone) and ratio free 5alpha-dihydrotestosterone over total 5alpha-dihydrotestosterone (percentage free 5alpha-dihydrotestosterone) were compared in healthy female volunteers. Treatment was randomly distributed over the volunteers; 11 women received Org 2969 + EE and 11 women received levonorgestrel + EE. These combinations induced similar increases in transcortin levels (115 and 140%) and ceruloplasmin levels (115 and 123%) after 3 months of treatment. However, the combination Org 2969 + EE induced a substantial increase (213%) in SHBG capacity after 3 months of treatment, whereas a smaller increase (80%) was observed with levonorgestrel + EE. A return to pretreatment values was observed 2 months after termination of treatment for all parameters. The difference in the effects of both preparations oh SHBG was statistically significant and can be best explained by a difference in the androgenicity of the progestogens. A good correlation was free testosterone and the reciprocal value of the percentage free 5 alpha-dihydrotestosterone. These results confirm that SHBG is the major regulator of the biologically active free androgen fraction in women before, during and after combined oral contraceptive treatment.

Menstrual blood loss with contraceptive subdermal levonorgestrel implants.

Six Silastic capsules each containing 30 mg of levonorgestrel were inserted subcutaneously in the left forearms of 13 volunteer women for contraceptive purposes. Quantitative determinations of menstrual blood loss were performed during a control cycle and during a 1-month period at the 1st, 6th, and 12th months of treatment. Days on which bleeding and spotting occurred were recorded and hemoglobin concentrations were determined. No changes were found in the amount of menstrual blood loss between the control cycles and the treatment cycles. The mean number of bleeding days during each of the three recorded treatment periods was significantly greater than that in the control cycles. No changes in hemoglobin concentration were found. None of the patients became pregnant during the study.

PIP: 6 silastic capsules, each containing 30 mg of levonorgestrel, were inserted subcutaneously in the left forearms of 13 volunteer women for contraceptive purposes. Quantiative determinations of menstrual blood loss were performed during a control cycle and during a 1-month period at the 1st, 6th, and 12th months of treatment. Days on which bleeding and spotting occurred were recorded and hemoglobin concentrations were determined. No changes were found in the amount of menstrual blood loss between the control cycles and the treatment cycles. The mean number of bleeding days during each of the 3 recorded treatment periods was significantly greater than that in the control cycles. No changes in hemoglobin concentration were found and none of the patients became pregnant during the study.