Statement on Norplant subdermal contraceptive implant system

At its September 1985 meeting, the International Medical Advisory Panel of the International Planned Parenthood Federation drafted a statement concerning Norplant, the subdermal contraceptive implant system developed by the Population Council. The statement, intended for use by physicians, administrators, and other health personnel in the field of family planning, summarizes current knowledge of this means of fertility control. Norplant is particularly recommended for women who seek longterm protection from pregnancy, but either may desire another child in the future or do not wish to undergo sterilization. Insertion during the 1st 7 days after menstruation onset, or immediately postabortion or postpartum (in nonbreastfeeding women), is advised. Capsules should be removed after 5 years of use. Annual pregnancy rates range from 0.2-1.3/100 women/year, with a cumulative pregnncy rate of 5 years of 2.6. The most frequently reported side effect is irregular menstrual bleeding, especially during the 1st year of use. Continuation rates are 60-90% at the end of the 1st year, and about 50% after 5 years. Counseling, especially regarding bleeding irregularities, is critical to continued acceptability. 40% of women who request Norplant removal in order to conceive become pregnant within 3 months of removal, and 76% achieve pregnancy within 1 year. Epidemiologic studies of the longterm safety of Norplant implants are under way. It is noted that program use of Norplant poses several managerial challenges. Formal training in insertion and removal techniques, as well as the risks and benefits of the method, must be planned and back-up and referral facilities identified. Since Norplant is a new delivery system, a carefully designed public information system is also important.     

Efficacy and side effects of Norplant use in Thai women above the age of 35 years.

A prospective study of Norplant implant use in women aged above 35 years was conducted in Bangkok, Thailand. The purposes of this study were to evaluate the efficacy, menstrual patterns, and side effects of Norplant use in these women. A total of 100 women were recruited in a 1-year clinical study. Their mean age was 39.7 years. Most acceptors had completed secondary school. No accidental pregnancy occurred throughout the 1 year of use in this study. The most common menstrual pattern in these acceptors was amenorrhea followed by irregular bleeding. The major side effect was irregular bleeding. There was no significant change in systolic and diastolic blood pressure during the 1 year follow-up period. Thus, Norplant implant use in older women is a safe and effective contraceptive method. This should become another choice for contraception in women aged above 35 years who have contraindications for oral contraceptive use.     

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.     

Prospective multicentre study comparing levonorgestrel implants with a combined contraceptive pill: final results.

Norplant is a hormonal, long term method of contraception requiring the sub-dermal placement of six flexible capsules containing levonorgestrel in the inner aspect of the upper non-dominant arm. This open, prospective, multicentre, parallel group study, comparing the acceptability of Norplant and a combined pill, was originally designed to follow 700 subjects for five years, but was discontinued early. The main outcome criteria were duration of use and reason for discontinuation if appropriate. This final analysis, concerning the 364 subjects who used the implant and 307 subjects who used a gestodene/ethinyloestradiol combined pill, shows a statistically significantly higher (p<0.001) continuation rate amongst the implant users at 83.4 per cent compared to the pill users at 64.4 per cent at one year and this difference decreased only slightly by two years. The most common reasons for discontinuation by the end of the study were adverse events in both groups (menstrual and then mood changes in the implant group and mood changes and then headaches in the pill group). From the whole cohort the proportion which were 'very satisfied' were higher in the implant group (28.5 per cent compared to 14.6 per cent). This study confirms, in the UK, a high continuation rate for implant users similar to other countries as reported in the literature. If acceptability and continuation rates are similar in the none study setting, then a substantial number of women will seek removal of the implant and possible reinsertion five years after the time of initial high popularity (ie 1999). Doctors need to be prepared for this possible high level of activity.     

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.     

Norplant® implants in the UK: First year continuation and removals

Norplant^® implants are a long-term, reversible hormonal method of contraception consisting of six flexible capsules placed subdermally in the inner aspect of the nondominant arm. Norplant implants were introduced into the UK in October 1993 although they had been used previously in some countries for up to ten years. The insertion and removal techniques require skills training and therefore it is important to assess early experience with the method.

This survey looks at the first year continuation rate of Norplant implants in the UK from a total of 2,129 insertions. From these insertions, 133 removals were documented and described, using a checklist of features. The continuation rate for Norplant implants use was 96.5% at six months and 85.2% at one year. None of the reasons for discontinuation were of a serious nature. The most common reason given was menstrual change (50.4% of all removals, 3% of all women included in the survey), which is in line with other reported studies.

Of the removals, 71.5% were reported as straightforward (of these 65.6% were completed within 20 minutes). In the first year of use, Norplant implants were associated with high continuation rates and the removal procedure was, in the majority of cases, completely straight-forward.     

国产皮下埋植剂多中心研究

目的:评价两种国产皮下埋植剂的避孕效果、副反应和继续使用率。方法:分两期进行。第一期为国产Ⅰ型、Ⅱ型皮下埋植剂与Norplant进行前瞻性临床对比研究,各100例,共300例。第二期为国产皮下埋植剂扩大临床应用,接受合格对象Ⅰ型999例,Ⅱ型998例,共1997例。随访5年。结果:5年随访率为99.5％。第一期国产Ⅰ型、Ⅱ型皮下埋植剂和Norplant的5年累计妊娠率分别为0/百妇女、1.0/百妇女、0/百妇女,5年继续使用率分别为77％、80％、80％,差异均无统计学意义(P>0.05)。主要副反应为月经紊乱,月经卡分析显示3种埋植剂的出血模型相似。第二期国产Ⅰ型、Ⅱ型皮下埋植剂5年累计妊娠率分别为0.20/百妇女,2.10/百妇女,5年继续使用分别为84.47％、82.28％。使用埋植剂6个月Ⅰ型和Ⅱ型月经问题主诉发生率分别为50.88％、57.16％,差异有显著意义(P<0.01),但随着使用时间延长,月经紊乱主诉发生率逐渐下降,两组间无差异。结论:5年研究表明两种国产皮下埋植剂的避孕效果、副反应发生率和继续使用率与Norplant相似,也是一种高效,长效的避孕制剂。国产皮下埋植剂Ⅱ型使用至第5年避孕失败率明显增加,建议国产Ⅱ型皮下埋植剂使用期限在3～4年为好。     

Norplant contraceptive implants: a new contraceptive for women

This article summarizes current knowledge on the mechanism of action, side effects, and effectiveness of Norplant contraceptive implants. The most common side effect of the implant method is its disruption of the menstrual cycle, especially in the 1st few months of use. Long intervals without frank bleeding may occur and be misinterpreted as pregnancy in women who have not been counseled about this possibility. The average annual continuation rate was 84/100 in a study of 324 women from several countries who were followed for 5 years after Norplant implantation. The net cumulative pregnancy rate for the 5-year study period was 0.6/100. Reasons for method termination included menstrual problems, other medical problems (headache, depression, fatique), planning pregnancy, and other personal reasons (change in marital status, change in residence). To provide training for doctors, nurses, and counselors, the Population Council has established a network of 5 training institutions. Within the next few years, drug regulatory agencies are expected to approve use of Norplant implants in many countries. Although at present the method is available only in Finland and Sweden, Thailand and Indonesia are considering the method and clinical trials are underway in India, China, Brazil, and the US. A consulting committee of the World Health Organization has concluded that Norplant implants are a suitable contraceptive method for use in family planning programs.     

Use of Norplant implants in the immediate postpartum period among asymptomatic HIV-1-positive mothers

A prospective cohort study of Norplant use in the immediate postpartum period among asymptomatic HIV-1-positive women was conducted in Bangkok, Thailand. The objectives of this study were to evaluate side effects and menstrual patterns of the Norplant system in this group. A total of 88 asymptomatic HIV-1-positive mothers were recruited for this study. All of them voluntarily accepted the use of the Norplant implant as a contraceptive method immediately postpartum. Their mean age was 24.9 years. Most of them had completed primary school. The follow-up period was 24 weeks. There were eight participants lost from the study because of loss of contact. Irregular bleeding was the most common menstrual pattern in these participants. The major side effects were headache, followed by hair loss. No subject terminated Norplant use during the study period. The Norplant implant appears to be safe and well tolerated in asymptomatic HIV-1-positive parturients when inserted immediately postpartum.     

皮下埋植避孕剂临床多中心对比研究

对两种国产皮下埋植避孕剂与 Norplant 进行前瞻性临床对比研究,以了解在避孕效果、临床副反应及续用率方面有无差异。全国10个省市分别承担国产Ⅰ型、Ⅱ型和 Norplant 各100例,采用前瞻性、随机化的临床对比研究。根据统一的科研计划、记录表格和定期随访,资料集中统计和处理。共接收国产Ⅰ型1 001例,国产Ⅱ型1001例,Norplant 998例。一年时的随访率为99.3%,1年内避孕失败1例,因各种原因的终止率分别为每百名妇女3.9、3.7和3.9,因月经问题而终止者分别占总终止的79%、73%和77%,一年末的续用率分别为96.1%、96.3%和96.1%,三组之间均无差异。两种国产皮下埋植剂均为一种高效的避孕方法,副反应发生率、因症终止率和续用率均与 Norplant 相似,在全国不同地区、不同群体之间和 Norplant 一样具有较高的可接受性,可供广大育龄妇女选用。     

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.     

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。     

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.     

国产18甲基炔诺酮皮下埋植剂的临床研究

666例40岁以下健康育龄妇女所参加的前瞻性多中心研究,经过一年观察,国产组333例中无妊娠,对照的Norplant-1组发生1例妊娠,妊娠率0.3/100妇女,二组的续用率同为94/100妇女。     

Norplant in The Netherlands

An 18-year old patient bearing a subcutaneous Norplant implant in the left upper arm for 2 years visited a gynecological clinic. The implant rods were removed under local anesthesia because of the increasing pigmentation of the skin, and she switched to oral contraceptive use. Norplant contains a total of 216 mg of levonorgestrel (LNG) in 6 silastic rods, each 3.4 cm long. Norplant-2 consists of 3 rods with a length of 4.4 cm providing a total of 140 mg of LNG. It has been in use since 1974 in Chile, and subsequently in Brazil, Indonesia, Thailand, Africa, and to a lesser extent in Scandinavia. It works via the continuous release of 30-50 mcg doses of progesterone daily that induces cervical mucous changes whereby sperm penetration is thwarted; nidation does not occur, and ovulation is also often inhibited. The Pearl-Index reaches .1-1.1 in the first 5 years of use. The most important side effects are menstruation changes (oligo- and amenorrhea), weight gain, and headache. The continuation rate is similar to that of the IUD: 95% through the 1st year of use, and 75% through 3 years reported from Chile and China. Reversibility is a major advantage: 50% of women become pregnant within 3 months after removal, 86% within 1 year, and 93% within 2 years. In the Netherlands sits acceptance is clearly distinct from prevalence in Chile and China, and it has only a minor role in applicability when other contraceptives fail.     

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.     

Effects of a subdermal levonorgestrel contraceptive implant (Norplant) on serum cholesterol, triglycerides, ALT and AST in Iranian women

BACKGROUND: To evaluate the effects of Norplant (36 mg of levonorgestrel, six capsules) on serum cholesterol, triglycerides, alanine transaminase (ALT) and aspartate transminase (AST), we enrolled 465 healthy women from Zahedan, Iran, into a longitudinal study. MATERIALS AND METHODS: Blood samples were collected after an overnight fast before implant insertion and after 3, 6, 9 and 12 months of use. RESULTS: Total cholesterol and triglyceride levels did not significantly change during Norplant use. Although there were statistically significant increases in ALT and AST levels during Norplant use, the values were within the reference range.     

Implantable contraceptives for women: effectiveness, discontinuation rates, return of fertility, and outcome of pregnancies

Progestogen-only contraceptive implants are highly effective. In most studies, 5-year cumulative pregnancy rates are less than 1.5/100 women for Norplant and Norplant II. No study has yet reported any failures with Implanon. Weight over 70 kg and age at insertion under 25 years both increase the failure rate of Norplant and Norplant II; however, data are as yet lacking for Implanon. The effectiveness of other progestogen-only implants for which there are as yet few data are unlikely to be any different. Continuation rates are high compared with other hormonal methods and with the intrauterine device. In most cohorts at least 35% of women, and often many more, are still using Norplant by the end of 5 years. Rates vary according to a number of factors, including population studied, age, and parity. Menstrual disturbance is by far the most common reason for discontinuation, with headache, acne, weight gain, and desire for pregnancy accounting for other common reasons for implant removal. Fertility returns rapidly following implant removal, and pregnancy rates (76-100% 1 year after removal) are usually no different from those following discontinuation of any other contraceptive method. There is no increase in the risk of ectopic pregnancy, fetal malformation, or impaired infant health in pregnancies conceived either during implant use or after removal.     

Norplant

Norplant capsules and Norplant 2 rods contain levonorgestrel (LNG) that is released slowly for up to 2000 days. After removal the progestogen vanished from the blood stream within 96 hours, and fertility is restored in contrast to the pill contraceptives. Norplant provides a cervix barrier against spermatozoa. About 1/2 of women taking it had anovulation or luteinization of unruptured follicles. In ovulating women the midluteal progesterone values were clearly reduced. There have been some reports concerning the increased aggregation of thrombocytes and the decline of high density lipoprotein (HDL) cholesterol levels in Norplant users. Thrombosis, cerebro- and cardiovascular accidents have not been reported. A longterm prospective study of Norplant 2 users showed an unacceptably high rate of pregnancies after the 4th year, thus the rods have to be replaced after 3 years instead of 5 years. 23% of Norplant 2 and 41% of Norplant users had to resort to removal because of side effects. 54% of Norplant and 48% of Norplant 2 users halted use after 3 years because of menstrual disorders, irregular bleeding, depression, and mood changes. LNG has high affinity to sex hormone binding globulin (SHGB), and it is not active in bound form. The free LNG index was lower in women with unwanted pregnancies than in other women. In 1989 the Population Council reported on 7 phase-3 investigations involving 2470 women. Only 398 completed the 5-year observation period: the cumulative pregnancy rate was 3.5, there were 3 pregnancies among those with body weight of 50-60 kg and 8.6 pregnancies among those weighing 70 kg or more. There were 101 unwanted pregnancies, and 1 child was born with intersexual genitals. Endometrium biopsy or curettage is advised in the event of irregular bleeding especially in women over 40, and about 25% of Norplant users have undergone these procedures.