Norplant contraceptive implants: rods versus capsules

Norplant contraceptive implants are silastic implants containing levonorgestrel. When placed subcutaneously in the medial aspect of the upper arm, they release low levels of levonorgestrel in a constant manner over an extended period of time. Comparative studies of two silastic rods versus six capsules containing levonorgestrel were studied in 250 subjects for 4,464 months of use. Only one pregnancy occurred during the study. Side effect patterns were similar in both groups; the major side effect being irregular uterine bleeding. The bleeding, however, was well tolerated by subjects in both groups and discontinuation rate was very low. The two-rod system offers the advantages of easier insertion technique and shorter insertion time as well as ease of removal as compared to the six-capsule system. Norplant contraceptive implants offer a highly effective means of contraception which is particularly suited for women who are concerned about failure and compliance with oral contraceptives. This type of contraception should become well accepted, not only in underdeveloped countries, but in developed countries as well.     

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.     

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.     

Immediate postabortal contraception with Norplant: levonorgestrel, gonadotropin, estradiol, and progesterone levels over two postabortal months and return of fertility after removal of Norplant capsules

Six Silastic levonorgestrel-releasing capsules, Norplant, were introduced subcutaneously into the ventral aspect of the left forearm or upper arm of thirteen patients immediately after first trimester pregnancy termination. Blood samples were taken twice a week over two months after abortion and from one subject over one month after removal of Norplant capsules. Plasma concentrations of levonorgestrel were measured by radioimmunoassay and the effects of treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone. If removal of Norplant capsules took place because of planning pregnancy, the subjects were asked to inform us if they had become pregnant. During the first month after abortion the mean levonorgestrel concentration (489 pg/ml) was statistically significantly higher than during the second month (237 pg/ml). The mean estradiol values fell to prefollicular levels within four days, remaining a little suppressed. The mean progesterone concentrations were below 2 ng/ml three days after abortion. Three subjects had a transient increase in plasma progesterone concentrations nine days after abortion. Thereafter no ovulatory progesterone concentrations were seen. The LH concentrations ranged within normal values of the follicular phase and FSH values were just beneath the lower limit of follicular phase FSH values, apart from a few peaks, indicating mild suppression. After removal of Norplant capsules, progesterone concentrations increased to ovulatory levels fifteen days after removal. The Norplant capsules were removed from two subjects because of planning pregnancy and they delivered healthy babies 9.5 and 12.5 months after removal.     

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

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.     

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.     

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.     

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.     

Bleeding pattern, outcome of accidental pregnancies and levonorgestrel plasma levels associated with method failure in Norplant implants users

The aim of this study was to characterize the bleeding pattern, the outcome of pregnancies and the levonorgestrel plasma levels associated with method failures in Norplant implants users. Nineteen pregnancies are reported in 458 woman and 21,589 woman-months observed during the first eight years of Norplant use. Pregnancy rates increased slightly during the first six years of use, attaining a Pearl Index above three thereafter. All women who became pregnant had experienced a regular bleeding pattern in the six months preceding conception. Levonorgestrel plasma levels observed at different intervals before conception and during the conceptional cycle were similar to those observed in non-pregnant women at comparable intervals after Norplant insertion. The nineteen pregnancies ended in thirteen term deliveries, one premature delivery, three abortions and two ectopic pregnancies. No abnormalities were found in the infants. The two ectopic pregnancies are the only ones reported for Norplant users in The Population Council studies. The overall incidence is less than 0.8 per 1000 woman-years.     

Levonorgestrel plasma levels during continuous administration with different models of subdermal implants

Plasma concentrations of levonorgestrel were determined in women using subdermal levonorgestrel implants. One group had 6 Silastic capsules (NORPLANT), one group had 4 and one group had 6 covered Silastic rods for variable lengths of time. Levonorgestrel concentrations remained constant around 0.4 ng/ml up until 6 years of use in the Norplant group. The observation period was shorter for the covered rods; plasma concentrations were, however, constant around 0.55 ng/ml and 0.70 ng/ml for 3.5 years with the 4 rods and 6 covered rods, respectively. The difference in mean levonorgestrel concentrations between the three groups were statistically significant (p less than 0.0005). Plasma levels of levonorgestrel were twice to three times higher in blood obtained from the arm with the implants compared to the levels found in the other arm. The application of a tourniquet for variable periods before blood sampling did not influence the plasma concentrations of levonorgestrel.     

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.     

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.     

WHO 86925 Norplant上市后监测(中国部分)

本课题研究目的是对Norplant皮下埋植剂潜在副作用进行监测,以进一步证实其安全性。对使用Norplant和IUD或绝育术的妇女进行比较随访研究。每半年随访一次,详细记录所有健康情况,共随访5年。随访率达99.9％。结果:Norplant组及对照组IUD和绝育术的5年继续使用率分别为76.25、80.89、98.10/100使用者。Norplant的5年累计妊娠率为0.6/100使用者,远低于IUD的8.11/100使用者,宫外孕发生率为0.46/1000妇女年,低于IUD的1.24/1000妇女年,但宫外孕和妊娠之比在Norplant组为31.6:100,远高于IUD的6.7:100,如发生妊娠,要警惕宫外孕的可能。月经问题是Norplant的主要终止使用原因,但使用5年者,其血红蛋白均值上升,和接收时相比P<0.001,而IUD使用5年者,其血红蛋白均值下降,和接收时相比P<0.01。在观察5年中胆囊炎胆石症、纤维囊性乳腺病在Norplant使用者中的发病率高于对照组,P<0.05～0.001,但未发现重大健康问题。Norplant使用5年是安全的。     

Endometrial vascularization in levonorgestrel intrauterine device users; computerized microvessel measurement study

Levonorgestrel use in the levonorgestrel intrauterine device (LNG-IUS) induces vascular distension within the superficial layer of the endometrium and massive pseudodecidualization. With a computer-assisted image analysis system, we objectively measured the vascular bed in LNG-IUS users and compared it to the physiological endometrium. A study was undertaken on 25 women using LNG-IUS, in an outpatient procedure at the time of removal of the IUS and compared with 11 normally cycling women (control group). Suction curette specimens were obtained just after retrieval of the IUS, and immunohistochemistry was carried out with a specific marker of the endothelial cells (CD31). Number of vessels decreased in the LNG-IUS group to 60/mm2 versus 124/mm2 in the control group, and mean vessel area increased to 1255 microm2 versus 157 microm2, respectively, in the control group. The decrease in mean vascular density and the increase of mean vessel area in the LNG-IUS group, compared to the control group, were both highly significant (p<.001).     

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.     

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.     

Potential barriers to the removal of Norplant among family planning clinic patients.

OBJECTIVES: This study examined the prevalence and effects of potential barriers to removal of levonorgestrel implants (Norplant) among low-income women. METHODS: A sample of 687 women who received Norplant at hospital-based family planning clinics were interviewed before Norplant insertion and 6 months after Norplant insertion (or at Norplant removal if removal occurred earlier). Those who continued to use Norplant were reinterviewed at 2 years or at removal. RESULTS: In a multivariate analysis, only 1 of the 4 potential barriers--cost--significantly impeded Norplant discontinuation. CONCLUSIONS: Family planning clinics need to make clear that they follow a policy of Norplant removal on demand, regardless of the patient's ability to pay.     

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.     

Effect on pregnancy rates of the delay in the administration of levonorgestrel for emergency contraception: a combined analysis of four WHO trials

Background

Levonorgestrel is an effective method for emergency contraception (EC) and is used worldwide. Consistent with its mechanism of action in delaying ovulation, the earlier it is administered within 72 h of an unprotected act of intercourse, the more effective it is. There is uncertainty, however, about its effectiveness after 72 h. This analysis explores the effect of 24-h intervals of delay in levonorgestrel administration on pregnancy rates when used until 120 h of an unprotected act of intercourse.

Study Design

Data were analyzed from 6794 women participating in four World Health Organization randomized trials and receiving 1.5 mg of levonorgestrel for EC in a single dose or split into two doses 12 h apart, within 48, 72 or 120 h of an act of unprotected intercourse. The pregnancy rates among women in successive days after an unprotected act of intercourse and odds ratios of pregnancy were calculated using logistic regression with the first day as the reference.

Results

For the four trials combined, odds ratios for pregnancy in the second, third and fourth day with respect to the first day were not significantly different from 1 at the 5% level of significance. On the fifth day, the odds ratio of pregnancy compared to the first day was almost 6.

Conclusions

Levonorgestrel for EC should be administered as soon as possible after unprotected intercourse. Delaying levonorgestrel administration until the fifth day after unprotected intercourse increases the risk of pregnancy over five times compared with administration within 24 h. It is uncertain whether levonorgestrel administration on the fifth day still offers some protection against unwanted pregnancy.