Biran Affandi

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.

Five-year experience with Norplant®☆

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.

Multicenter clinical trial on the efficacy and acceptability of a single contraceptive implant of nomegestrol acetate, Uniplant

Uniplant, a single Silastic implant containing nomegestrol acetate, provides contraceptive efficacy for one year. Uniplant use for one year was studied in 1,803 healthy women of reproductive age, enrolled from 10 centers in 9 countries, after informed consent. Implants were placed subdermally either in the upper arm or in the gluteal region. Two-hundred-seventy-six subjects discontinued prior to completing one year of study. Cumulative discontinuation rate at 12 months was 15.72%. Medical reasons for discontinuation were principally menstrual-related. Fifteen pregnancies occurred during the one year study period, resulting in a 12-month net cumulative pregnancy rate of 0.94%. Approximately 56% of subjects using Uniplant had bleeding patterns similar to normal menstruation. Results from this study confirm that Uniplant is an efficient, well tolerated, 12-month contraceptive implant, with the advantage of easier insertion and removal of the single implant compared to other multiple implant methods.

A multicentred phase III comparative study of two hormonal contraceptive preparations given once-a-month by intramuscular injection: II. The comparison of bleeding patterns

A multicentred Phase III clinical trial was conducted in 12 countries to compare HRP112 (depot-medroxyprogesterone acetate, 25 mg and estradiol cypionate, 5 mg) and HRP102 (norethisterone enantate, 50 mg and estradiol valerate, 5 mg) given every 28 days. Contraceptive efficacy and side-effects of both regimens were reported previously. Their effect on vaginal bleeding patterns is the object of this paper. A total of 2320 women were randomly assigned to each drug and 2000 of them provided a menstrual diary. The comparison of the bleeding patterns is made using a 90-day reference period approach and following the guidelines published by WHO. The analysis failed to identify any major difference in the vaginal bleeding patterns induced by both contraceptive preparations. For both drugs, the first bleeding episode following the first injection occurs early. For 70% of users, this is followed by a regular vaginal bleeding pattern similar to an untreated pattern. Others experience irregular bleeding and a few have either infrequent or frequent bleeding. The extremes of amenorrhea and prolonged bleeding are rare. There are no major trends in vaginal bleeding patterns with prolonged use of either preparation. Women with the worst vaginal bleeding patterns discontinue early in the clinical trial and the last three months of experience have the most influence in their decision to stop using the contraceptive method. The analysis suggests how the life-table analysis of discontinuation reasons underestimates the true incidence of vaginal bleeding irregularities in a clinical trial.

The ‘frameless’ intrauterine system for long‐term, reversible contraception: A review of 15 years of clinical experience

Aim:  The development of the ‘frameless’ intrauterine system (IUS) is a response to the growing need to develop high‐performing, long‐acting, reversible, and acceptable contraceptives with a high continuation of use.

A pilot efficacy study with a single-rod contraceptive implant (Implanon®) in 200 Indonesian women treated for ≤4 years

In this 4-year open-label, noncomparative, single-center pilot efficacy study, the contraceptive efficacy, safety, bleeding pattern and acceptability of Implanon was studied in 200 sexually active women of proven fertility in Indonesia. All subjects received the single-rod subdermal implant Implanon, which contains 68 mg etonogestrel (3-keto-desogestrel), with an initial release rate of 67 micrograms etonogestrel/day. Contraceptive efficacy was analyzed by calculation of the pregnancy rate, bleeding patterns were determined by the 90-day reference period method, and acceptability by the discontinuation rate. No in-treatment pregnancies were reported during 658.4 women-years of exposure, resulting in a Pearl Index of 0.0 (95% CI 0.0-0.6). The overall bleeding pattern was acceptable, with no discontinuations because of irregular bleeding. Incidence of irregular bleeding was highest during the first two reference periods and decreased thereafter. Amenorrhea was experienced by 7%-12% of subjects during years 1 and 2, by 5%-7% during year 3, and by 2%-5% during year 4, with one discontinuation because of amenorrhea. No clinically significant changes were reported for systolic and diastolic blood pressure, body mass index, and hemoglobin level. Three adverse experiences were related to treatment and resulted in discontinuation (two headaches and one dyspnea). One difficult implant removal was reported. In conclusion, this pilot efficacy study indicates that Implanon provides excellent contraceptive reliability and an acceptable bleeding pattern. Overall safety and acceptability are good, as suggested by the low incidence of adverse experiences and the low discontinuation rate.

The effects of Implanon® on lipid metabolism in comparison with Norplant®

This open, randomized study was intended to assess the effects of the new single-rod contraceptive implant (Implanon) containing etonogestrel on lipid metabolism in Indonesian women, in comparison with the six-rod implant Norplant, containing levonorgestrel. The effects of both products were compared with a control group using an intrauterine device (IUD) over a 3-year period. A total of 135 healthy volunteers of childbearing potential, aged 22 to 41 years, were enrolled in Jakarta, Indonesia. Ninety volunteers were randomized to use Implanon (n = 45) or Norplant (n = 45), and a nonrandomized group of 45 Multiload Cu 250 IUD users served as a control. Serum concentrations of total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apolipoprotein AI, apolipoprotein AII, and apolipoprotein B were measured. The ratios of HDL cholesterol to total cholesterol, of HDL to LDL cholesterol, and of apolipoprotein AI to apolipoprotein B were determined. Lipid and lipoprotein determinations were done at screening and after 3, 6, 12, 18, 24 and 36 months. Contraceptive efficacy and insertion and removal times were also recorded. Mean changes from baseline in the lipid and apolipoprotein parameters, although occasionally statistically significant, were small in all groups (less than 1 standard deviation of the mean concentration at baseline) and clinically not significant. Statistically significant differences between the Implanon and Norplant groups were only occasionally observed. In both implant groups, total mean cholesterol, LDL cholesterol, and apolipoprotein AI concentrations tended to decrease during the study, but statistically significant changes from baseline were only occasionally observed, suggesting that drug-related factors are not involved. The mean ratios of HDL/total cholesterol and the HDL/LDL cholesterol showed very little change over time in both implant groups; slight and statistically nonsignificant increases were noted at most time points. Similar changes were seen in the group of IUD users. It can be concluded that changes from baseline in the lipid and apolipoprotein parameters tested were generally small and did not differ between Implanon and Norplant.

Pregnancy after removal of NORPLANTR implants contraceptive

Many concerns have been expressed regarding the introduction of a new contraceptive method into family planning programmes. One of the concerns is the return of fertility after discontinuing the method. To evaluate the subsequent fertility status of the Indonesian women after removal of Norplant, a prospective longitudinal study was undertaken in Klinik Radeb Saleh, Jakarta. Fifty-one women whose Norplant were removed because of their wish to become pregnant were followed-up for a period of two years or until pregnancy occurred, whichever was earlier. Two groups of women who had Lippes C IUD removed or discontinued the use of DMPA for planning pregnancy served as control and were followed-up for equal length of time. The cumulative conception rate for ex-Norplant users, ex-IUD users and ex-DMPA users at one year was 76.5, 74.7 and 70.2 per 100 women, respectively. There was no significant difference between the groups (p greater than 0.05). The present study, along with other studies, indicate that the prolonged use of Norplant do not impair the return of fertility.

Expression of the chemokines, monocyte chemotactic protein (MCP)-1 and MCP-2 in endometrium of normal women and Norplant® users, does not support a central role in macrophage infiltration into endometrium

The endometrium contains many leukocytes, including macrophages, the numbers varying with the time of the menstrual cycle and being maximal peri-menstrually. The long-acting progestogenic contraceptive Norplant, has a high rate of discontinuation due to uterine bleeding; this is associated with large numbers of endometrial macrophages. Monocyte chemotactic proteins (MCP) act to recruit and activate monocytes into sites of inflammation. This study compared the cellular localization of endometrial MCP-1 and MCP-2 across the normal menstrual cycle and in users of Norplant. Both MCP-1 and MCP-2 were present in normal endometrium, but with very different patterns of cellular location and considerable variability between individuals. MCP-1 of epithelial origin was present in 77% of tissues, while stromal staining was present in 52% and vascular staining in 34% of samples. MCP-1 was also released from both epithelial and stromal cells in culture. MCP-2 staining was predominantly epithelial and was found in 52% of tissues while stromal staining was present in only 3/56 samples. Vascular staining of MCP-2 was found in 2/56 samples. The epithelial staining was mostly punctate and sometimes within uterine secretions. No correlation of staining for MCP-1 or -2 with the phase of the cycle was found in any cellular compartment. Very little immunoreactive MCP-1 or MCP-2 was detected in endometrium from Norplant users regardless of morphological subtype. These distributions do not support a role for either MCP-1 or MCP-2 in the migration of macrophages into the endometrium and suggest that these cytokines may have other functions in this tissue.

The interaction between sex hormone binding globulin and levonorgestrel released from Norplant an implantable contraceptive.

Two-hundred-and-eighty Indonesian women were provided with Norplant, a levonorgestrel-releasing implant. At various time intervals, up to 5 years after Norplant insertion, levonorgestrel and sex hormone binding globulin (SHBG) were assayed in blood plasma. After an initial burst of approximately 7 nmol/l, the levels of levonorgestrel rapidly decreased during the first month. The decrease continued to a nadir (1.1 nmol/l) which was reached 10 months later. The decrease was followed by an increase to a broad peak of 1.5 nmol/l which was reached 2 years after insertion. Thereafter, a slow-decrease at a rate of approximately 18 pmol/month was seen. SHBG levels decreased significantly already 1 week after insertion. A nadir of levels (25 nmol/l) was reached 3 months later. The levels increased slowly again and remained constant (32 nmol/l) from about 15 months to 5 years. During the entire period of study highly significant correlations of levonorgestrel with SHBG were seen. In another group of 25 women the levels of levonorgestrel and SHBG were studied before and one week after insertion of Norplant. A significant correlation (r = 0.77) was found between the preinsertion levels of SHBG and postinsertion levels of levonorgestrel.