Post-marketing surveillance of Norplant contraceptive implants: I. Contraceptive efficacy and reproductive health

The subject of this study to examine the safety and contraceptive efficacy of Norplant, we undertook a 5-year study of follow-up of women initiating use of Norplant, intrauterine device (IUD) or sterilization in eight developing countries. Women attending family clinics were enrolled if they consented and were medically eligible to use Norplant, IUD, or female sterilization. Women who chose to initiate use of IUDs or surgical sterilization served as controls and were frequency matched in 5-year age-bands with women who chose to use Norplant. At admission women had a physical examination, and their medical histories, demographic, and socio-economic characteristics were recorded. Follow-up visits were scheduled in the first 6 weeks after admission and semi-annually thereafter for 5 years irrespective of change of contraceptive method. Incidence rate ratios of health events were estimated for initial and current contraceptive method use. This paper reports reproductive health events and contraceptive efficacy. Altogether, 7,977 women initiating use of Norplant, 6,625 of IUD, and 1,419 of surgical sterilization were admitted. Their mean ages at initiation were 28.5, 28.5, and 29.6 years, respectively. More than 99% were married or cohabiting, and parous. Five-year follow-up was completed by 94.6% of the women. By the end of 5 years, the mean duration of first segment use per initiator was 4.16 years for Norplant, 4.10 years for IUDs, and 4.96 years for sterilization accounting for 39,337 woman-years for Norplant, 31,915 for IUDs, and 7,071 for sterilization. The study accumulated 78,323 woman-years of observation. Pearl pregnancy rates for Norplant, copper IUDs and female sterilization were 0.27, 0.88, and 0.17 per 100 woman-years, respectively. Users of Norplant, copper IUDs, and sterilization had rates of ectopic pregnancy of 0.30, 0.68, and 0.13 per 1,000 woman-years, respectively. Major health events related to the reproductive system were rare. Rates of acute PID were significantly lower among Norplant users than IUD users (p = 0.004). The rate of ovarian enlargement was significantly higher in Norplant users than controls (p <0.001), but not rates of hospitalization for this condition. Vaginitis and vaginal discharge, and low abdominal pain were significantly less frequent in Norplant users than in the other groups. Bleeding disturbances were more frequent among Norplant users than controls but not anemia. The study confirms the high contraceptive efficacy of Norplant, copper IUDs, and female sterilization. The incidence rates of major reproductive health problems were low. There was no significant excess of serious reproductive morbidity among users of Norplant compared to users of IUDs and sterilization.     

Prolonged effectiveness of Norplant(R) capsule implants: a 7-year study

Soft tubing Norplant(R) contraceptive implants were studied in 1210 women for 7 years to measure the duration of effectiveness and the magnitude of the pregnancy rates over that time. Mean age at enrollment was 27.4 years. Of the enrollees, 42% were US residents. One-sixth (16.1%) weighed >/=70 kg at the time of implant placement. At the end of 5 years, the cumulative pregnancy rate was 1.1/100; at the end of 7 years, it was 1.9/100. No pregnancies occurred to any of the 400 women who enrolled in the study at age >/=30 years and who weighed <100 kg. Among women aged 18-33 years, the 7-year Norplant pregnancy rates are comparable to the median pregnancy rates of tubal sterilization methods for women of the same age and duration of use. For women aged >/=34 years, without regard to weight at admission, the 7-year effectiveness of soft tubing Norplant equals or surpasses that of tubal sterilization. For continuing implant users, annual pregnancy rates <1.0/100 in years 6 and 7, together with low cumulative pregnancy rates, testify that Norplant capsule implants remain highly effective for 7 years.     

Health and growth of infants breastfed by Norplant contraceptive implants users: a six-year follow-up study

The objective of the study was to evaluate safety to infants whose mothers used Norplant levonorgestrel implants during breastfeeding. A nonrandomized clinical trial design was used. Participants were 220 and 222 healthy breastfed infants of mothers initiating use of Norplant or T-Cu IUD, respectively, at 55 days to 60 days postpartum. Infants were followed from birth through age 6 years. Breastfeeding pattern, infant growth, and disease events were recorded monthly in the first year, three-monthly in the second, and annually thereafter. Most mothers continued use of Norplant (96.4%) and T-Cu (94.1%) during lactation, and 2140 months of infant exposure to levonorgestrel were accumulated. Breastfeeding pattern and infants growth, from admission through age 6 years, were similar in both groups. In the first year, breastfed infants in the Norplant group had higher incidence rates (p < 0.05) of mild episodes of respiratory infections (adjusted RR 1.17, CI 1.08-1.27), skin conditions (adjusted RR 1.46, CI 1.20-1.79), and eye infections (unadjusted RR 1.49, CI 1.03-2.18) than the control group. Later on, a higher proportion of infants in the T-Cu group showed neurological conditions. Although breastfeeding patterns and infant growth is not affected by Norplant use during lactation, the effect on infants' health of steroidal contraception should be further evaluated.     

Effect of etonogestrel subdermal contraceptive implant (Implanon) on liver function tests -- a randomized comparative study with Norplant implants

OBJECTIVE: The study aimed to assess the possible differences in effects of Implanon and Norplant implants on liver function over 2 years of use. METHODS: This is a 2-year open randomized study of 80 implant (Implanon and Norplant) acceptors. Selected parameters of liver function were tested in the serum before implant insertion and at 6, 12 and 24 months after implant insertion. RESULTS: In both the implant groups, the mean total and unconjugated bilirubin and the gamma-glutaryl transferase levels were significantly raised during implant use. For none of the subjects, at any sampling period, did the levels exceed the normal range in our population. There was no significant elevation of any other liver enzymes in either group. CONCLUSION: It appears that there may be mild hepatocellular dysfunction associated with the use of both Implanon and Norplant, which is possibly of no clinical significance to the healthy acceptor.     

Focal brachial cutaneous neuropathy associated with Norplant use: suggests careful consideration of the recommended site for inserting contraceptive implants

A case of neuropathy in the medial antebrachial cutaneous nerve of the forearm following a Norplant(R) removal is described. The incidence of this problem is uncertain. The suggested sitting of the contraceptive implants directly over the bicipital groove is questioned.     

Provision of contraceptive implants in school-based health centers: A cost-effectiveness analysis

ObjectiveTo evaluate the cost-effectiveness of providing contraceptive implants in school-based health centers (SBHCs) compared to the practice of referring adolescents to non-SBHCs in New York City.Study DesignWe developed a microsimulation model of teen pregnancy to estimate the cost-effectiveness of immediate provision of contraceptive implants at SBHCs over a 3-year time horizon. Model parameters were derived from both a retrospective chart review of patient data and published literature. The model projected the number of pregnancies as well as the total costs for each intervention scenario. The incremental cost-effectiveness ratio was calculated using the public payer perspective, using direct costs only.ResultsThe health care cost of immediate provision of contraceptive implants at SBHCs was projected to be $13,719 per person compared to $13,567 per person for delayed provision at the referral appointment over 3 years. However, immediate provision would prevent 78 more pregnancies per 1000 adolescents over 3 years. The incremental cost-effectiveness ratio for implementing in-school provision was $1940 per additional pregnancy prevented, which was less than the $4206.41 willingness-to-pay threshold. Sensitivity analyses showed that the cost-effectiveness conclusion was robust over a wide range of key model inputs.ConclusionProvision of contraceptive implants in SBHCs compared to non-SBHCs is cost-effective for preventing unintended teen pregnancy. Health care providers and policymakers should consider expanding this model of patient-centered health care delivery to other locations.     

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.     

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.     

Ovarian function during use of Nestorone(R) subdermal implants

Nestorone(R) progestin (NES) is a potent 19-nor-progesterone derivative which is biologically inactive when administered orally; however, it is an excellent option for implant contraception. The objective of this study was to evaluate ovarian function during use of either one 4-cm or two 3-cm NES implants for 24 months. A total of 60 volunteers were enrolled in each dose group. Vaginal ultrasound (VUS) and blood sampling for determinations of estradiol (E(2)), progesterone (P) and NES serum levels were carried out twice a week for 6 consecutive weeks, beginning in months 1, 6, 12, 18, and 24 of implant use. Serum levels of NES declined with time, with a more pronounced decrease during the first 18 months of implant use; thereafter, NES levels remained stable until the end of the study at 24 months. Luteal activity was very infrequent during the first year of use (<3%) but increased during the second year, occurring in 27% and 35% of the sampling periods in the 1-implant group, and 2% and 16% of the sampling periods in the 2-implant group, at months 18 and 24 of use, respectively. No luteal activity was observed with NES levels above 80 pmol/L. Serum P levels in periods of luteal activity were significantly lower than those of controls. Persistent anovulatory follicles were the most common VUS finding and this was associated with E(2) levels that remained within the normal range (101-1500 pmol/L) in the majority of the sampling periods studied. Considering that a single implant offers advantage for insertion and removal, a new single NES implant is being developed with a slightly higher release rate, to reduce effectively the incidence of ovulation and provide a greater margin of safety beyond 2 years.     

Effective use of hormonal contraceptives: Part II: Combined hormonal injectables, progestogen-only injectables and contraceptive implants

Our objective in this systematic review was to evaluate evidence regarding controversial issues in the clinical management of women using injectable and implantable contraceptives. We searched MEDLINE and EMBASE for reports of primary research, published from 1966 through April 2005 in peer-reviewed journals, related to the initiation of combined or progestogen-only injectables and contraceptive implants, the effects of late contraceptive injections or the duration of levonorgestrel implant effectiveness. Results of the studies we reviewed showed that initiating injectable and implantable contraceptives through day 7 of the menstrual cycle suppresses follicular activity. Time to ovulation after study participants discontinued using injectables varied widely: from 4 to 8 weeks after the last administration of combined injectables, from 15 to 49 weeks after the last injection of depot medroxyprogesterone acetate and from 5 to 19 weeks after the last injection of norethisterone enanthate. Norplant implants left in place for up to seven completed years remained effective among women who weighed <70 kg at the time of implant insertion, but their effectiveness decreased among women weighing >or=70 kg.     

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.     

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.     

Sentinel Health Events (occupational): a basis for physician recognition and public health surveillance.

A Sentinel Health Event (SHE) is a preventable disease, disability, or untimely death whose occurrence serves as a warning signal that the quality of preventive and/or therapeutic medical care may need to be improved. A SHE (Occupational) is a disease, disability, or untimely death which is occupationally related and whose occurrence may: 1) provide the impetus for epidemiologic or industrial hygiene studies; or 2) serve as a warning signal that materials substitution, engineering control, personal protection, or medical care may be required. The present SHE(O) list encompasses 50 disease conditions that are linked to the workplace. Only those conditions are included for which objective documentation of an associated agent, industry, and occupation exists in the scientific literature. The list will serve as a framework for developing a national system for occupational health surveillance that may be applied at the state and local level, and as a guide for practicing physicians caring for patients with occupational illnesses. We expect to update the list periodically to accommodate new occupational disease events which meet the criteria for inclusion.     

Effect of oral contraceptive agents on nutrients: II. Vitamins.

Clinical, biochemical and nutritional data were collected from a large population of women using oral contraceptive agents. Higher incidence of abnormal clinical signs related to malnutrition were observed in the lower (B) as compared to the higher (A) socioeconomic groups, and also in the nonsupplemented groups as compared to the supplemented groups in the B subjects. As a rule the intake of oral contraceptive agent subjects of vitamin A, C, B6 and folic acid did not differ from that of the controls As expected, subjects from the supplemented groups had higher intake of vitamin A, C, B6, thiamin, riboflavin and folic acid, and A groups had higher intake of vitamin C, B6, riboflavin and folic acid. Increased plasma vitamin A and decreased carotene levels were observed in oral contraceptive agent users. In general oral contraceptive agents had little or no effect on plasma ascorbic acid. Urinary excretion of both thiamin and riboflavin in subjects using oral contraceptive agents were lower in A groups. Erythrocyte folate and plasma pyridoxal phosphate was decreased in A groups due to oral contraceptive agents. Subjects who took supplements had higher levels of plasma vitamin A, ascorbic acid and folate. But urinary thiamin and riboflavin were higher only in group A subjects who took supplements.