Phase II randomized comparative clinical trial of Norplant (six capsules) with Norplant-2 (two covered rods) subdermal implants for long-term contraception: report of a 24-month study. National Programme of Research in Human Reproduction

In a randomized clinical study, contraceptive efficacy and bleeding patterns were studied in a group of healthy, regularly menstruating, non-lactating women (n = 84) using two 4.4 cm covered silastic rods containing levonorgestrel, Norplant(R)-2, and compared with another group of women (n = 88) using six 3.4 cm capsules also containing levonorgestrel, Norplant(R). The silastic rods or capsules were placed subdermally in the medial aspect of the upper arm. No method failure was reported up to 24 months of use in this study with either of the device. The bleeding pattern was also similar for both devices as indicated by average episode length, number of bleeding runs and number of spotting days. The continuation rates with both devices were over 80 per 100 users at the end of 12 months and over 65 per 100 users at the end of 24 months. Discontinuations due to expulsion of the device, bleeding problems or personal reasons were few and similar for both devices. The results suggest that silastic-covered rods, Norplant(R)-2, which are comparatively easier to insert and remove and have similar clinical effect, could replace capsules, Norplant(R), as a long-term reversible subdermal contraceptive.     

NorplantR contraceptive subdermal implants: Two-year experience in Singapore

Norplant contraceptive implants are Silastic containing levonorgestrel implants. This study describes our two-year experience with 100 acceptors of Norplant implants in Singapore. No pregnancies occurred during the first two years of use. Desire for planned pregnancy and disruption of menstrual rhythm were the two main reasons for twenty implant removals during the two years. The continuation rate at the end of two years was 79%. The post-removal conception rate in women desiring pregnancy was 90% at the end of one year. It thus appears that the Norplant contraceptive system offers a highly effective, acceptable, reversible and safe method of contraception.     

Where next with long-acting steroids?

A new generation of steroidal contraceptives is undergoing clinical trials or has reached the stage of national drug authority approval. In November 1983, Norplant contraceptive implants were approved for marketing in Finland as a longacting contraceptive. Norplant continues to be evaluated in large-scale clinical trials in a number of developing and developed countries. A continuous low dose of levonorgestrel is released into the woman's blood from 6 small silastic capsules implanted under the skin of the arm. A variation using 2 implants is under study. The implant systemmay be used for up to 5 years. The mechanism of action of levonorgestrel has 3 components: inhibition of ovulation in about 1/2 of cycles, suppression of the endometrium, and alteration of the cervical mucus to make it less permeable to sperm. The annual pregnancy rate is about .5/100 women. Fertility returns rapidly after removal, and the implant system has a good safety profile. The most frequent side effects in the 1st months of use are apparently menstrual irregularity or spotting, but total blood loss may be decreased. The steroid does not influence blood pressure and hasno unfavorable effect on blood lipids. The Population Council, developer of Norplant, is expected to seek US Food and Drug Administration approval on the basis of specific clinical experience. A vaginal ring consisting of a 3-layer ring of silastic containing levonorgestrel and estradiol has also been developed by the Population Council. The 2 hormones are released into the vagina at a constant rate and absorbed into the woman's blood, resulting in inhibition of ovulation. The rings imitate the action of combined oral contraceptives but do not require daily administration. The World Health Organization is also developing a vaginal ring which contains only a progestogen and is worn without a 1-week break in use. A new sustained-release formulation of norethindrone (NET) is entering expanded clinical trials in the US and developing countries. The system consists of biodegradable polymeric microspheres containing NET which are injected intramuscularly as a suspension. Depending on the size of the microspheres the product can provide 30,90, or 180 day contraceptive protect ive with a single dose. The availability of the 3 formulations each with different durations of action will serve the contraceptive needs of varied populations. Most longacting steroidal contraceptives give rise to menstrual irregularities, but they have the convenience of long action and the physiological advantage of low doses delivered directly to the systemic circulation. Use by millions of women for 1-2 decades will be required before they are completely understood.     

Effect of Norplant contraceptive on the bones of Nigerian women as assessed by quantitative ultrasound and serum markers of bone turnover

Levonorgestrel is a commonly used progestin-only contraceptive that is available as subdermal (Norplant) and intrauterine implants. Other progestin-only contraceptives such as injectable medroxyprogeterone acetate have been shown to decrease bone mineral density in long-term users. We used calcaneal ultrasound to compare the bone quality of Nigerian women between 25 and 50 years of age who had Norplant implants for 1-4 years to that of women who were not using any form of hormonal contraceptive. The mean stiffness index of women who had Norplant implants for as long as 4 years was not significantly different from that of controls. However, serum markers of bone turnover were significantly decreased in women with Norplant implants compared to age-matched controls. Serum bone-specific alkaline phosphatase was significantly decreased in subjects with Norplant implants for 1 year (13.7+/-6.0 vs. 23.0 U/L for controls, p = .001) and serum NTx was significantly decreased in subjects with implants for 3 years (10.6+/-4.9 vs. 17.6+/-7.7 bone collagen equivalents per liter for controls, p < .001). We conclude that although levonorgestrel contraceptive decreased overall bone turnover, it had no deleterious effect on the bone quality of women using Norplant implants for up to 4 years.     

A longitudinal study of changes in endometrial microvascular density in Norplant implant users.

This study aimed to investigate the effects of the subdermal levonorgestrel contraceptive implant Norplant on endometrial vascular density at different durations of exposure, and the relationship between endometrial histology, vascular density, and bleeding patterns. A prospective controlled trial of Norplant implant users compared endometrial vascular density in biopsies taken before and after Norplant implant insertion. A total of 34 women with regular menstrual cycles requesting long-term contraception were recruited at the Sydney Centre for Reproductive Health Research, Australia. A significant increase in mean endometrial microvascular density was observed from as early as 3 weeks after insertion of Norplant implants. Vascular density was increased from a control secretory phase value of 189.6 (7.0 vessels/mm2 (+/- SEM) to 253.80 +/- 7 vessels/mm2 at 2-13 weeks of Norplant implant exposure (t ratio = 2.08, p = 0.01) and 212.7 +/- 12.9 vessels/mm2 at 14-42 weeks of exposure (t ratio = 2.03, p = 0.02). In those with atrophic endometrium, or in whom myometrium and basalis only were found in biopsies (20 of 66, 30%), mean endometrial vascular density was increased at 273.1 +/- 16.1 vessels/mm2 compared with 210.9 +/- 11.7 vessels/mm2 in other histological groups (F ratio = 9.74, p = 0.0028). Bleeding and spotting in the previous 30 days were less common in those with this histological appearance at a mean of 4.95 days compared with 8.22 days. This is the first study to assess endometrial vascular density in the early months of Norplant implant use. The findings suggest that the endometrial vasculature is profoundly altered in the early months of Norplant implant exposure when bleeding problems are most common.     

Plasma levels of levonorgestrel in women during longterm use of Norplant

Levonorgestrel plasma levels were determined by a specific radioimmunoassay in a group of 110 women at various intervals between 1 and 60 months fallowing implantation of six silastic capsules containing levonorgestrel (Norplant). The implants were placed subdermally in the volar aspect of the forearm. Blood samples were taken twice a week for six consecutive weeks in each subject. Blood drawn from the antecubital vein ipsilateral to the implant site contained two to three times more levonorgestrel than contralateral samples. Average systemic plasma levels represented by contralateral samples ranged from 0.35 ± 0.03 to 0.29 ± 0.02 ng/ml (Mean ± S.E.) in the first and fifth year, respectively. The difference between these values is statistically significant at the 5% level. The results of the regression analysis of individual levels suggest that the decline observed throughout the first five years is mainly due to an early decrease taking place in the first two years. When the sampling period was repeated in the same subjects two or three times 10 to 24 months apart, no significant difference was found. A significant negative correlation was found between plasma levonorgestrel levels and body weight and body surface. The data indicate that the contraceptive efficacy of Norplant during the first five years of use is associated with sustained release of levonorgestrel and is in keeping with the estimated life span of Norplant of seven years.     

Facts about an implantable contraceptive: Memorandum from a WHO Meeting

This Memorandum reviews the results of research undertaken in animals and human subjects on the implantable contraceptive, Norplant, and where relevant, its components, levonorgestrel and Silastic. Results from clinical trials, including effectiveness and side-effects, are evaluated and service delivery aspects commented on. The Memorandum concludes with a statement regarding the use of Norplant as an option for long-term reversible contraception.     

IMAP statement on Norplant subdermal contraceptive implant system

The Norplant implant system consists of 6 silastic capsules which deliver levonorgestrel to protect against pregnancy over 5 years. Clinical trials were conducted in 46 countries. The 5-year cumulative pregnancy rate is 3.9%. Norplant's efficacy falls as weight increases. Its failure rate is lower than that of combined oral contraceptives and most IUDs. Counseling is linked to acceptability. Medical personnel should be trained in counseling potential Norplant acceptors. They must undergo formal training in insertion and removal of Norplant. The first year and fifth year continuation rates are 75-90% and 25-78%, respectively. Bleeding irregularities are the main reason for discontinuation and the most commonly reported side effects. Levonorgestrel changes the cervical mucus and suppresses ovulation and the endometrium. Toxicological and teratological data on levonorgestrel and silastic show that Norplant is safe. It appears that Norplant does not cause any major pathological changes in the endometrium, liver, kidney, and adrenal and thyroid glands. Levonorgestrel in Norplant is linked to a slight increase in serum glucose levels which are not of significant consequence. Its effects on lipids and lipoproteins are not clear. Fertility returns to Norplant users shortly after removal. The return to fertility pattern basically matches that of other methods. Contraindications of Norplant use are confirmed or suspected pregnancy, previous ectopic pregnancy, breast cancer, cancer of the genital tract, cerebrovascular or coronary artery disease, acute liver disease, and undiagnosed abnormal genital bleeding. Norplant should be inserted subdermally in the upper arm during the first 7 days after menstruation begins. The capsules must be removed after 5 years if pregnancy is to be avoided. Before family planning programs provide Norplant, managers should make sure the staff is adequately prepared. Health personnel, counselors, potential users, and the public need informational materials on Norplant.     

A multicenter comparative study on the efficacy, safety, and acceptability of the contraceptive subdermal implants Norplant and Norplant-II

In order to assess efficacy, safety, and acceptability of the contraceptive subdermal implants Norplant^® and Norplant^®-II in Mexican women, a comparative phase III clinical trial was undertaken in eight clinics across the country. The study involved 1052 women who were followed-up trimonthly for three years. Cumulative pregnancy rates were 0.29% and 0.34% for Norplant and Norplant-II implants, respectively. Similar overall cumulative discontinuation rates were observed at three years: 50.38% for Norplant capsules, and 50.44% for Norplant-II rods. The main method-related reason for termination was endometrial bleeding irregularity which led to discontinuation rates of 11.94% and 11.62% for Norplant and Norplant-II contraceptive systems, respectively. In 15,279 woman-months of experience accumulated with Norplant implants and 14,092 with Norplant-II implants, there were few adverse events reported. No difference was found between the two groups in either difficulty for implants placement and removal or women's discomfort, even though the time required for insertion and removal of Norplant capsules was longer than for Norplant-II rods. It is concluded that during the first three years of use, both implants systems are equally effective, safe, and acceptable.     

A randomized multicenter study comparing the efficacy and bleeding pattern of a single-rod (Implanon) and a six-capsule (Norplant) hormonal contraceptive implant.

To compare the contraceptive efficacy, tolerability, and bleeding patterns, 200 healthy female volunteers received, in an open, comparative, randomized, multicenter study in China, either a single-rod (Implanon) or a six-capsule (Norplant) contraceptive implant for 2 years with an optional extension of up to 4 years. Women were exposed to Implanon for 341.6 woman-years and Norplant for 329.1 woman-years. There were no pregnancies during the study. Per 90-day reference period, the median number of bleeding/spotting days with Implanon decreased from 33.5 in the first period to 19.0-21.5 days in the last year. Similarly, with Norplant, the median number of bleeding/spotting days decreased from 34.5 to 18.0-23.0 days, respectively. The number of bleeding/spotting episodes during year 1 was 2.0 per 90-day reference period with Implanon and 3.0 per period with Norplant (p < 0.05 for periods 1-4). For the remaining 90-day periods, there was no statistical difference between the two groups. In general, there was less frequent bleeding with Implanon compared with Norplant, whereas the incidences of amenorrhea and infrequent bleeding were higher with Implanon than with Norplant. The mean overall incidence of prolonged bleeding fell markedly during the study, from 66.0% in reference period 1 to 27.3% in period 16 with Implanon and from 69.0% to 21.7% with Norplant, respectively. The most common adverse events were related to disturbed bleeding patterns, which were also the major reasons for discontinuation (Implanon n = 8; Norplant n = 14). Normal menses returned in almost all subjects within 3 months after removal of the implants. Implanon was inserted in a mean time of 0.61 min and Norplant in 3.90 min (p < 0.001). Similarly, the mean time required to remove the implant was significantly shorter for Implanon than for Norplant (2.18 min vs 11.25 min, p < 0.001). The maximum time required for removal of the implant was 10 min for the Implanon group and 60 min for the Norplant group. In both groups, blood pressure and hemoglobin were not affected, whereas body weight tended to increase. It can be concluded that both contraceptive systems demonstrated excellent contraceptive efficacy and were well tolerated. Compared with Norplant, there was less frequent bleeding with Implanon, whereas the incidence of infrequent bleeding and amenorrhea was higher. Implanon was significantly quicker to insert and to remove than was the multiple capsule system.     

Contraceptive implants and lactation

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.     

Use of Norplant implants in a New York City clinic population

Two-hundred-eight women attending family planning clinics in New York City who received the Norplant contraceptive system during the first sixteen months of Norplant implants insertions were evaluated. Within this clinic population, Norplant implants were a popular contraceptive choice and were removed from 64 of the 208 recipients. Reasons for removal included bleeding, weight gain, and headache, and were consistent with those found in the clinical trials. Prior satisfaction with oral contraceptives did not predict success or failure with Norplant implants. The rate of follow-up visits to the family planning clinics was low. However, evidence exists that these women did not lose contact with the medical center and continued to receive health care.     

1 056例皮下埋植避孕剂取出原因分析

目的：探讨皮下埋植避孕剂取出原因与取出年龄和放置时间的关系。方法：对1994年1月—2014年12月在本所门诊取出皮下埋植避孕剂的1 056例育龄妇女进行取出原因分析,比较不同取出年龄段及不同放置时间的因症取出原因的构成比。结果：1 056例皮下埋植避孕剂取出人群中,539例期满取出,395例因月经异常取出,97例因除月经外其他不适取出,23例因计划妊娠或改用其他避孕方法取出,2例在有效期内避孕失败取出。皮下埋植避孕剂取出原因构成比在不同取出年龄组中差异有统计学意义（P＜0.05）,在不同放置时间组中差异无统计学意义（P＞0.05）;其中不同取出年龄和放置时间组中,月经异常和头痛、痤疮等其他症状的构成比差异均有统计学意义（P＜0.05）,计划妊娠或改用其他避孕方法的构成比差异无统计学意义（P＞0.05）。结论：皮下埋植避孕剂是持久、高效、简便的避孕方法,月经异常和头痛、痤疮等症状是不同年龄段和放置时间皮下埋植避孕剂取出的主要原因。     

Timing of onset of contraceptive effectiveness in Norplant implant users. II. Effect on the ovarian function in the first cycle of use.

The objective of this study was to time the onset of contraceptive effectiveness in Norplant implant users, when the capsules were inserted beyond the first 7 days of the cycle, based on the immediate effect on the ovarian activity. A total of 42 healthy women requesting Norplant implant contraception were enrolled at clinics in Santo Domingo, Dominican Republic, and in Baltimore, Maryland. Implants were inserted on days 8-13 of the menstrual cycle. Blood samples for estradiol (E2), progesterone (P), luteinizing hormone (LH) (in a subset of 12 women), and levonogestrel (LNG) assay, were taken at 0 h and at 6, 12, 24, 72, and 168 h postinsertion. Ovulation, as defined by P > 2.5 ng/mL, occurred in 40% of subjects. A short lasting, frequently blunted, LH peak occurred within 12 h postinsertion, in all these subjects. The remaining subjects had anovulatory cycles with two distinct E2 profiles: continuously increasing E2 levels to a high mean of 414.3 pg/mL (28%), or no sustained increase in E2 (32%). Most cycles (86%) in which Norplant was inserted with high E2 levels (> 175 pg/mL) were ovulatory, whereas none were ovulatory with low E2 (< 100 pg/mL) at insertion. Based on the endocrine effects of Norplant implant insertion in the midadvanced follicular phase, in which ovulation will either occur within 48 h of insertion or will be impaired, additional contraceptive protection is necessary only for 3 days.     

Norplant皮下埋植避孕150例临床研究

目的:探讨Norplant皮下埋植避孕的效果。方法:选择Norplant皮下埋植避孕妇女150例作为治疗组,以宫内节育环避孕妇女150例作为对照组,比较两组使用情况、避孕效果和月经紊乱情况。结果:5年后随访,治疗组因不适取出32例,取出率为21.33%,其余118例全部达到避孕效果,有效率100.00%;期间出现月经紊乱58例,发生率为49.15%;对照组因不适取出或自行脱出10例,取出率为6.67%,其余140例中达到避孕效果115例,有效率82.14%,出现月经紊乱33例,发生率为23.57%。两组避孕效果、月经紊乱和不适失败率比较均具有统计学差异(P<0.01)。结论:对生育期要求避孕妇女行皮下Norplant埋植避孕手术可达到有效的避孕效果,但月经紊乱发生率相对较高,宫内节育环避孕有效率较皮下Norplant埋植避孕手术低,但月经紊乱发生率亦较治疗组低。使用Norplant埋植避孕如何减少月经紊乱,仍是今后值得探讨的一个问题。     

A five-year clinical evaluation of NORPLANT contraceptive subdermal implants in Bangladeshi acceptors

A non-comparative study of the Norplant contraceptive subdermal implant system was conducted in Dhaka, Bangladesh. The study was designed to evaluate the contraceptive efficacy, safety and overall acceptability of Norplant implants. Six hundred women were enrolled in the clinical trial, which began in 1985 at three study sites. Follow-up visits were scheduled at 1, 3, and 6 months after Norplant implant insertion, and every six months thereafter until removal or at the end of five years. There were no post-insertion pregnancies during Norplant implant use in this study. After five years of Norplant implant use, there was no clinically significant change in body weight, systolic or diastolic blood pressure. Less than 3% of the women ever reported having any significant medical problems such as migraine, respiratory or cardiac problems during the study. The gross cumulative continuation rate was 41.2 per 100 women at the end of five years. The two most frequently reported reasons for discontinuation during the study were menstrual problems and desired pregnancy. Of the women who completed the five-year user satisfaction questionnaire, the majority of the women (86.3%) planned to continue using contraception after study completion. Of these women, approximately one-third said they planned to use another Norplant set. The findings presented suggest that the Norplant system is a highly effective, safe and acceptable method among Bangladeshi women.     

Norplant: what health educators need to know

The US Food and Drug Administration approved the contraceptive implant Norplant in December 1990. Many US physicians and nurse practitioners have received training in inserting the implant, but few health educators know enough about Norplant and potential users to provide adequate education and counseling. The 6-capsule system steadily releases 50-80 mg levonorgestrel into the bloodstream for five years for a contraceptive effectiveness rate greater than 99%. Levonorgestrel keeps the pituitary gland from releasing two hormones needed for ovulation, thickens the cervical mucus, and suppresses endometrial development. Irregular bleeding is the most common side effect. Contraindications for Norplant include liver tumors, active liver disease, breast cancer, active thrombophlebitis, unexplained uterine bleeding, pregnancy, blood clots in the eyes or lungs, diabetes, hypertension, and cigarette smoking. Advantages are its 5-year effectiveness period, that it is easy and convenient to use, does not require compliance, and is reversible. Disadvantages are that it offers no protection against sexually transmitted diseases, especially HIV/AIDS; it requires a surgical procedure; and its cost ($500-$750/patient). Few studies present a profile of US women using Norplant. Potential users are adolescents, vulnerable women, low income women with children, and women who do not want to become pregnant for a long time but do not consider the pill or sterilization viable options. Extensive research indicates that Norplant is safe in the short and intermediate term. More research is needed to identify the demographic profile of a typical user, why she chooses Norplant, how well she understands it, or whether she was well informed about it; to learn about satisfaction with Norplant; and to find out who discontinues Norplant before the end of 5 years. This information would help health educators in their counseling and education strategies.     

Ovulation detection following removal of levonorgestrel subdermal contraceptive implants

The time to resumption of ovulation following the discontinuation of levonorgestrel subdermal implants (Norplant) was assessed in 10 women. A blood sample (2 ml) was taken at the time of Norplant removal and then twice weekly until the first evidence of ovulation (serum progesterone concentration greater than or equal to 5 ng/ml) was documented. Ovulation was resumed in 80% of the cases by 3 weeks and in all the cases by 7 weeks. Prompt return of ovulation following Norplant removal is an additional advantage of this mode of long-acting contraception.     

Plasma levels of levonorgestrel in women during longterm use of norplants

Levonorgestrel plasma levels were determined by a specific radioimmunoassay in a group of 110 women at various intervals between 1 and 60 months following implantation of six silastic capsules containing levonorgestrel (Norplant). The implants were placed subdermally in the anterior aspect of the forearm. Blood samples were taken twice a week for six consecutive weeks in each subject. Blood drawn from the antecubital vain ipsilsteral to the implant site contained two to three times more levonorgestrel than contralateral samples. Average systemic plasma levels represented by contralateral samples ranged from 0.35 0.03 to 0.29 0.02 ng/ml (Mean ± S.E.) in the first and fifth year, respectively. The difference between these values is statistically significant at the 5% level. The results of the regression analysis of individual levels suggest that the decline observed throughout the first five years is mainly due to an early decrease taking place in the first two years. When the sampling period was repeated in the same subjects two or three times 10 to 24 months apart, no significant difference was found, A significant negative correlation was found between plasma levonorgestrel levels and body weight and body surface. The data indicate that the contraceptive efficacy of Norplants during the first five years of use is associated with sustained release of levanorgestrel and is in keeping with the estimated life span of Norplants of seven years.     

Hormonal implants: the next wave of contraceptives

It will soon be possible for a woman who does not want to become pregnant to have a Norplant system implanted under the skin of her arm; it provides a 5-year supply of continuous hormonal contraceptive protection. Failure rates have been consistently below 1 pregnancy/100 users/year, and the system has generally shown continuation rates at least as good as IUDs. As with other contraceptives using progestins alone, the implant tends to disrupt menstrual patterns; a large proportion of women who stop using the method do so because of abnormal bleeding. However, menstrual disturbances appear to subside toward the end of the 1st year of use. The system consists of 6 separate capsules about 1.3 inches long and .1 inches in diameter made of silastic packed with 36 mg of levonorgestrel. Every day about 30 mg. of this hormone are released. The capsules are inserted in a fan-shaped pattern after a .2 inch incision is made; the entire operation, including preparing the patient and administering a local anesthetic, requires 10-15 minutes. Removing the implants is somewhat more complicated as the layer of fibrous tissue that forms around them must 1st be cut open. This procudure may take up to 20 minutes. The return of fertility does not appear to be compromised by the use of the implant. The 6-capsule Norplant system may be replaced in a few years by a more advanced 2-rod version that is now undergoing clinical trials.