From 1987 to 1997, approximately four million Indonesian women had a Norplant insertion. Concerns have been raised about the timely removal of the implant within a few days of the user's request or at the end of the recommended five years of use and about the possibility of a large and rapidly increasing backlog of removal cases developing. This study of 2,979 Indonesian women in 14 provinces, all of whom had had Norplant inserted five or more years before they were interviewed, reveals that 66 percent had obtained removal by the end of the fifth year of use and 90 percent had done so by the end of the sixth year of use. The data from this study strongly suggest that no large backlog of removal cases exists, particularly after the sixth year of use. The major reason for the underreporting of removals is probably clients' use of nurse/midwives, of caregivers in the private sector, and of mass safari camps, because records from each of these sources are poor or nonexistent.

Norplant implants were removed from fifty (50) patients using a modified approach to Norplant implant removal (Emory Method). Eighty-eight percent (88%) of the removals were accomplished in less than 10 minutes using this technique. The average time for removal of Norplant implants from 50 women included in the current study was 8 minutes. The Emory Method for Norplant implant removal includes three steps which are different from the technique developed by the Population Council. More anesthesia, a slightly longer incision and vigorous disruption of the tissue encapsulation surrounding the implants are recommended. The Emory Method is fast, safe and easy to perform. It has been successfully taught to over twenty-five clinicians.

OBJECTIVE

To identify the effects of temperament and character on the selection of contraceptive methods.

METHODS

Cross-sectional study carried out in June 2005 at the Ondokuz Mayis University Samsun Health College with the participation of 102 young women. The participants were asked to complete the Contraception Choice Questionnaire devised by the researchers, and the Cloninger Temperament and Character Inventory.

RESULTS

The mean age of the participants was 22.30 +/- 1.27 years; 39 participants (38.2%) mentioned Norplant, 30 (29.4%) condoms, 17 (16.6%) intrauterine devices (IUDs) and 16 (15.7%) oral contraceptives (OCs) as the method they would consider using in the future. The mean scores of self-directedness and self-transcendence of the groups differed significantly (p < 0.05). Students who indicated they would choose OCs had higher average scores for self-directedness than those choosing IUDs; the mean self-transcendence scores of students choosing IUDs were significantly higher than the scores of those selecting condoms (p < 0.01). Subjects choosing Norplant cited ease of use; those choosing condoms cited their eliciting fewer side effects; those choosing IUDs cited their high levels of safety; and those choosing OCs cited ease of use and high reliability as the reasons for their choices.

CONCLUSIONS

We think that identifying the roles of temperament and character in the selection process of a contraceptive method will help in achieving a wider application of contraception.

Vascular endothelial growth factor (VEGF) expression and the microvascular density of the endometrium were studied in Norplant users and normal controls, using immunohistochemistry on formalin-fixed paraffin-embedded endometrial sections. The VEGF staining index was quantified using computerized image analysis. The VEGF staining index between stages of the menstrual cycle and between normal and Norplant endometria were compared. Norplant VEGF staining index was analysed for correlation with microvascular density, duration of Norplant use, the number of bleeding/spotting days in the reference period up to 90 days prior to biopsy, and the length of time since the last bleeding/spotting episode. The results showed that immunoreactive VEGF was detected predominantly in endometrial glands but weakly expressed in the stroma throughout the menstrual cycle, and also in Norplant users. Large variation in the VEGF staining index between individuals was observed and no significant difference in the VEGF staining index was detected between stages of the menstrual cycle for the glands and stroma. The glandular and stromal VEGF staining indices were significantly higher in Norplant than in normal endometrium (P<1x10(-4)). No correlation was found between the Norplant VEGF staining index and endometrial microvascular density, duration of Norplant use, the number of bleeding/spotting days in the reference period, and the length of time since the last bleeding/spotting episode. The VEGF staining index was higher in glands than stroma for both normal and Norplant endometrium. The results suggest a differential control of endometrial glandular versus stromal VEGF expression, and possible positive effects of levonorgestrel on VEGF expression.

It has been shown that the endometrium of women using progestin-only contraceptives has increased vascular fragility, although the structural basis for this weakness is unknown, as is its role in breakthrough bleeding (BTB). Perivascular cells such as pericytes and vascular smooth muscle cells surround capillaries during the maturation process following angiogenesis, and act to strengthen and stabilize the vessels. The aim of the present study was to quantify endometrial perivascular smooth muscle alpha-actin (alphaSMA) expression in women using Norplant with and without BTB problems, and compare it to controls. Using immunohistochemical techniques, vessels were classified as level 0, 1 or 2 depending on whether perivascular alphaSMA was absent, discontinuous or continuous. In 15 controls the subepithelial plexus had significantly more level 0 vessels than either the functionalis or basalis (61 +/- 4 versus 31 +/- 6 and 37 +/- 4%, P = 0.0006 and P = 0.0007 respectively). In contrast the functionalis and basalis had significantly more level 2 vessels than the subepithelial plexus (20 +/- 3 and 23 +/- 2 compared to 4 +/- 1%, P = 0.0005 and P = 0.000 respectively). The major finding of the study was that in Norplant users, where the relatively atrophic endometrium cannot be divided into different regions, women with BTB problems (n = 20) had significantly more level 0 vessels than those with reduced bleeding (n = 17) (60 +/- 4 versus 46 +/- 4%, P = 0.0302). Norplant users with BTB problems also had a non-significant reduction in level 2 vessels compared to women without bleeding problems (4 +/- 2 versus 11 +/- 4%, P = 0.0667). These results demonstrate that perivascular alphaSMA is reduced around the endometrial vessels of Norplant users with BTB compared to those with no bleeding problems, and strongly support the concept that reduced vascular structural integrity plays a key role in endometrial BTB.

Contraceptive protection offered by a method depends on its duration of use, which reflects costs, side effects, and relatives' opinions. This study investigated in Norplant implants users the continuation rates, some of their determinants, and the motives for removals. Since 1988, 612 Norplant implants sets, designed to protect for 5 years, have been inserted. Observing 13,907 months of use, we determined over time the continuation rates and how age, parity, circumstances at insertion (postpartum, postabortum, others), and patronymic origins (surrogate for sociocultural factors) influenced them. Statistics included Kaplan-Meier's method and log rank tests, and uni- and multivariate Cox models. Continuation increased with age and depended on sociocultural factors. Parity exerted influence only in younger women. Median duration of use was 3 years 11 months. Removals before 5 years related almost equally to irregular bleeding, other side effects, and pregnancy wish. The cumulative 5-year failure rate was 1.5%. Unsatisfied users returned earlier, distorting the first results. A literature search showed that implants yield, in the mean, slightly better continuation figures than do intrauterine devices, and clearly higher than those obtained with pills and injectables. To optimize costs and counseling, warnings about the risk of short duration of use in young nullipara, especially if negative sociocultural influences prevail, are recommended. In no category are the implants absolutely to be avoided. Individual and programmatic contraceptive choice should take into account the expected continuation of use.

A clinical study was conducted to assess the effects of oestrogen in controlling increased endometrial bleeding problems in the first year of Norplant use. Three treatment groups were studied: (i) 50 micrograms ethinyl oestradiol (EE); (ii) a combined pill containing 30 micrograms EE and 150 micrograms levonorgestrel (LNG); and (iii) placebo. Based on menstrual diary records, women with prolonged, frequent or irregular bleeding, as defined by World Health Organization criteria, were randomly allocated to one treatment for 21 days. A first endometrial biopsy was taken before commencing treatment and a second biopsy at either day 14 or 21 of treatment. Following treatment, all subjects kept a menstrual diary card for 90 days. In this preliminary study, 48 subjects had completed the full 90 day post-treatment record. Within 21 days of EE treatment, the number of bleeding/spotting days was reduced significantly (P < 0.02). In the 90 days following treatment, the administration of EE and EE + LNG significantly decreased the number of bleeding/spotting days (P < 0.05). There was no reduction in the number of bleeding/spotting episodes in the EE and EE + LNG groups, but the length of each bleeding/spotting episode was significantly shorter (P < 0.05). Histopathological findings of endometrium on day 0 revealed consistent progestogenic effects, and there was no apparent change in response by day 14 or 21 of EE or EE + LNG treatment. The results of this study confirm the clinical effectiveness of EE and EE + LNG for the treatment of irregular, frequent and prolonged bleeding in Norplant users.

OBJECTIVE

Our purpose was to determine the safety and tolerance of levonorgestrel contraceptive implants (Norplant, Wyeth-Ayerst, Philadelphia) when inserted immediately post partum, to document the effects on weight and blood pressure, and to determine the side effects.

METHODS

After vaginal delivery, 250 women were randomized to receive Norplant within 48 hours of delivery (study group) or at the 4- to 6-week postpartum visit (control group). Baseline measurements were recorded and compared with those obtained at the 4- to 6-week follow-up visit. A diary was maintained by patients who recorded bleeding and side effects. Statistical analysis was performed with t test and chi 2 analysis.

RESULTS

There were no episodes of acute postpartum hemorrhage or clinically significant bleeding. Compared with the control group, the immediate group reported significantly more bleeding days (p < 0.01). There was no significant difference between the two groups in the hemoglobin values obtained at 4 to 6 weeks post partum. The immediate insertion group reported significantly more headaches (p < 0.01) and acne (p = 0.01).

CONCLUSIONS

Norplant is well tolerated and should be available for interested patients immediately post partum.

This report summarizes the data collected in pre-introductory Norplant implants clinical trials in 17 countries in Latin America, Asia and Africa that were coordinated by either the Population Council or Family Health International (FHI) between 1984 and 1991. A total of 16,282 women between the ages of 18 and 40 years participated in the studies with semi-annual or annual follow-up visits for up to 5 years. Gross cumulative pregnancy rates were < 0.6 per 100 women in the first year and < 1.5 in the second year in all countries. Significant differences in cumulative 5-year pregnancy rates were observed between weight groups 40-49 and 50-59 kg and between 50-59 and 60-69 kg body weight but not between 60-69 kg and those>> or = 70 kg. Total cumulative discontinuation rates after five years of Norplant implants use ranged from 35.8 to 60.0 per 100 women. Younger age and low parity were associated with a higher discontinuation rate. Cumulative discontinuation rates for menstrual reasons more than doubled between the end of the first year and second year of use in 13 of 17 countries. This analysis and one previous review provide the only comparison of Norplant contraceptive system study results across a wide diversity of countries; thus allowing an appreciation of the range of clinical experience with Norplant implants and the regional differences in that experience.

BACKGROUND

Progestin-only contraceptives (POCs) are appropriate for many women who cannot or should not take estrogen. Many POCs are long-acting, cost-effective methods of preventing pregnancy. However, concern about weight gain can deter the initiation of contraceptives and cause early discontinuation among users.

OBJECTIVE

The primary objective was to evaluate the association between progestin-only contraceptive use and changes in body weight.

METHODS

We searched MEDLINE, CENTRAL, POPLINE, EMBASE, LILACS, ClinicalTrials.gov, and ICTRP, and contacted investigators to identify other trials.

METHODS

All comparative studies were eligible that examined a POC versus another method or no contraceptive. The primary outcome was mean change in body weight or body composition.

METHODS

Two authors extracted the data. We computed the mean difference with 95% confidence interval (CI) for continuous variables and odds ratio with 95% CI for dichotomous variables.

RESULTS

We did not conduct meta-analysis due to the various contraceptive methods and weight change measures. Fifteen studies examined progestin-only pills (N=1), Norplant (N=4), and depot medroxyprogesterone acetate (DMPA) (N=10). Comparison groups were similar for weight change in 11 studies. Four studies showed differences in weight or body composition change for POCs compared to no hormonal method. Adolescents using DMPA had a greater increase in body fat (%) versus a group using no hormonal method (mean difference 11.00; 95% CI 2.64 to 19.36). The DMPA group also had a greater decrease in lean body mass (%) (mean difference -4.00; 95% CI -6.93 to -1.07). In another study, weight gain (kg) was greater for the DMPA group than an IUD group (mean difference 2.28, 2.71, 3.17, respectively). The differences were notable within the normal weight and overweight subgroups. One study showed the Norplant (six-capsule) group had greater weight gain (kg) than a non-hormonal IUD group (mean difference 0.47 (95% CI 0.29 to 0.65) and a group using non-hormonal or no method (mean difference 0.74; 95% CI 0.52 to 0.96). Another study also showed a Norplant group also had greater weight gain (kg) than an IUD group (mean difference 1.10; 95% CI 0.36 to 1.84).

CONCLUSIONS

We found little evidence of weight gain when using POCs. Mean gain was less than 2 kg for most studies up to 12 months, and usually similar for the comparison group using another contraceptive. Appropriate counseling about typical weight gain may help reduce discontinuation of contraceptives due to perceptions of weight gain.

OBJECTIVE

To update United States steroidal contraceptive use data for the period 1989 to 1994.

METHODS

Pharmaceutical marketing data were used to examine trends in the utilization and distribution of oral contraceptives, Norplant, and Depo-Provera.

RESULTS

There were 56.8 million prescriptions for oral contraceptives dispensed through retail pharmacies in 1994. Estrogen and progestin doses remained fairly stable over time. The average ethinyl estradiol dose of formulations was approximately 34 microg per pill. Mentions for oral contraceptives among 35- to 44-year-old women increased. Approximately 169,000 Norplant systems were distributed from 1991 through 1994. More than 1.5 million milliliters of Depo-Provera were distributed from 1993 to 1994.

CONCLUSIONS

Oral contraceptives remain a popular form of contraception. Parenteral formulations have been rapidly accepted.

A 1995 publication on serious adverse events in users of Norplant implants submitted to the Food and Drug Administration's MedWatch Spontaneous Reporting System reported 14 hospitalizations for stroke in Norplant users. This number was higher than expected. This is a report on the association of current use of Norplant implants with stroke and myocardial infarction (MI) based on a pooled analysis of data from two population-based, case-control studies conducted in the US. All data collection for these two studies occurred after approval of Norplant implants for marketing in the US in December 1990. The methods of the individual studies are detailed in prior publications.

Three cases of localized skin reaction in the first month after implantation of the Norplant contraceptive resulted in a partial implant expulsion and removal in one patient, and implant removal in another. Clinical evidence of infection was absent in all patients. While lidocaine with epinephrine was used in all three patients, the cause for these skin reactions remains unclear. Physicians should be alerted to the possibility of significant skin reactions associated with this procedure.

Attempts were made to collect several samples of cervical mucus in each of thirty-three cycles of women using NORPLANT subdermal implants, in seven cycles from NORPLANT-2 rod users, and in 33 control cycles. The attempts to collect a mucus sample were successful on 20 of 77 and 7 of 14 occasions in NORPLANT capsule and rod users, respectively, due to the scanty amount and stickiness found in the majority. All 59 attempts in control subjects were successful. The distance travelled by the fastest sperm and by the bulk of spermatozoa through the cervical mucus in vitro was assessed after 10 min of incubation with a normal semen sample. The best score for each cycle was considered for the comparison between treated and control cases. Sperm penetration was greatly impaired in mucus samples of implant users with penetration by the fastest sperm exceeding 10 mm in only two instances and exceeding 20 mm in none. In 30 of 33 control samples, the fastest sperm travelled 21 mm or more and in 28, the bulk of spermatozoa travelled further than 10 mm. Unsuccessful attempts to collect mucus and poor sperm migration were observed in NORPLANT implant users even when circulating estradiol levels were comparable to those seen in the late follicular phase of the normal menstrual cycle. These results suggest that the principal mechanism by which NORPLANT implants prevent pregnancy is by interference of sperm migration through cervical mucus.

This study utilized a mouse model to examine whether levonorgestrel implants, such as Norplant, may exert their contraceptive effects in part by adversely affecting oocyte quality. Time-release pellets and silastic capsules containing levonorgestrel were implanted subdermally in mice and left in situ for periods of two or three months. After that time, mice were given injections of gonadotropins to stimulate ovulation and oocytes were obtained from the oviducts of the animals, inseminated, and subsequently cultured for 96 hrs, some in medium supplemented with levonorgestrel. The numbers of oocytes that were fertilized and the numbers that developed at least to the morula stage were determined. Levonorgestrel was not found to have an adverse effect on either fertilization or preimplantation development but instead was found in some cases to increase the proportion of oocytes fertilized and the proportion of embryos that developed to morulae. Results indicate that the contraceptive effect of levonorgestrel implants should be attributed to effects other than diminished oocyte quality and they further substantiate the safety of levonorgestrel, suggesting that it will not adversely affect early embryonic development in the event that a pregnancy should be initiated during its use.

Steroids can be administered in at least five different ways: injectables; hormone-releasing intra-uterine devices (IUDs); implants; vaginal rings; and pills. Progestogens which are synthetic steroids, are used as the main bioactive substances. Different progestogens are effective for different periods of time. Progestins in daily oral pills are effective for 24 hours. The effectiveness of a progestogen can be prolonged by incorporating it in a sustained-release system that gradually releases the hormone; therefore they can be effective up to 5 years or more. Two progestogen-only injectables are widely available in the family planning programmes, (DMPA and NET-EN) and two combined injectables, Cyclofem (DMPA + EC), and Mesigyna (NET-EN + EV). The ring is placed by the woman in her vagina, where it gradually releases hormone. Implantable contraceptives are placed just under the skin on the inside of the woman's arm. Implant capsules release the progestogen at a slow, steady rate. There are three implantables available in the market: Implanon; Norplant; and Jadelle. They are effective for 1-5 years, but then must be replaced. Natural and synthetic progestogens were first added to IUDs in the early 1970s. The main problem of long-acting progestogens is the disruption of the menstrual cycle.

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.

This paper presents findings based on a five-year, noncomparative study of Norplant contraceptive subdermal implants in Nepal. The study was designed to evaluate the contraceptive safety, efficacy, and overall acceptability of Norplant. Four hundred and seven women enrolled in the clinical trial, which began in 1985, at two study sites, located in Patan and Kathmandu. Follow-up visits were scheduled at 1, 3 and 6 months after Norplant insertion and every six months thereafter until removal or at the end of five years. Although five pregnancies were reported during the study, only two women (one from each center) were diagnosed as becoming pregnant while using Norplant. The pooled gross cumulative life-table pregnancy rate was 0.6 per 100 women at the end of five years. The pooled cumulative continuation rate was 62 per 100 women at the end of five years. The three most frequently reported reasons for discontinuation were menstrual problems, personal reasons, and medical reasons. Of the 125 women who completed a five-year user satisfaction questionnaire, the majority of the women (86%) planned to continue using contraception after study completion. Of these women, almost one half said they planned to use a second Norplant set. The findings suggest that the Norplant system is a safe, effective, and acceptable method of contraception among Nepalese women.

Levonorgestrel implants (Norplant) have been recommended as a contraceptive method for teenage women. Our experience suggests that the use of Norplant implants in adolescents is associated with bleeding irregularities and modest weight gain. There is no effect on condom use or STD acquisition. Despite the bleeding irregularities, we documented high continuation rates, suggesting that with appropriate pre-insertion counseling, Norplant implants can be a successful contraceptive method for adolescent women.

Two-hundred-and-forty healthy women, ages 18 to 40 years, were randomized in a ratio of 2:5 to use NORPLANT implants or NORPLANT-2 implants. Through three years of use, no pregnancies were recorded among women using NORPLANT implants and two pregnancies were noted among women using NORPLANT-2 implants resulting in a cumulative net pregnancy rate of 1.3 +/- 0.9 per 100 acceptors (mean +/- SE) by the end of year three. This difference was not statistically significant. During the fourth year, no pregnancies were observed in the NORPLANT group, but 4 pregnancies occurred in the NORPLANT-2 group. The most common reason for terminating the study was bleeding disturbances. During the first year there were significantly more terminations due to bleeding problems in the NORPLANT group than in the NORPLANT-2 group. However, during the second year of use the proportion of women discontinuing for bleeding problems dropped considerably among NORPLANT users and during the third year very few women in either group discontinued because of bleeding problems. The continuation rates after one year were for NORPLANT users 59.4% and for NORPLANT-2 users 77.2%. Corresponding figures after three years of use were 46.1% and 51.7%, respectively. The second most common reason for discontinuation was depression and other mood changes. In both groups we noted a slight increase in weight during the study and a slight decrease in blood pressure and hemoglobin levels with time. In conclusion, both NORPLANT and NORPLANT-2 implants are very effective methods for contraception. The efficacy of NORPLANT-2 implants, however, was not acceptable during the fourth year of use in this study. The latter system could, however, become a suitable three-year contraceptive method, possibly with less bleeding disturbances than NORPLANT in the first year.