Levonorgestrel concentrations during 7 years of continuous use of Jadelle contraceptive implants.

Serum levonorgestrel concentrations were assayed in a multicenter, 7-year study of 199 users of Jadelle rod implants. We examined drug levels, patterns of changes, factors affecting drug levels, and concentrations at which pregnancies occurred. Mean levonorgestrel concentrations declined from 435 pg/mL at 1 month of use to 64% of that value (280 pg/mL) at the end of 3 years. Between the end of the third and fifth years neither mean nor median serum levels varied markedly. At 5 years the mean concentration was again 64% of the first month's mean. Declining levels were observed thereafter through the end of 7 years when the mean, 224 pg/mL, was 52% of the 1-month value. Last measured drug concentrations of women who became pregnant during Jadelle use had mean and median values of 152 and 144 pg/mL, respectively, and a maximum value of 180 pg/mL. Analyses indicated ponderal index, body weight, duration of use, and a single clinical center were the most important variables affecting measured levonorgestrel levels. Approximately one-third of assays in the sixth and seventh years were found to be below 180 pg/mL, suggesting that Jadelle levonorgestrel implants would not maintain sufficiently high levels of effectiveness against pregnancy after 5 years and that heavier women would then be at greater risk of pregnancy.

Contraception with two levonorgestrel rod implants. A 5-year study in the United States and Dominican Republic.

A 5-year trial of a two-rod contraceptive implant, which releases the progestin levonorgestrel (LNG rod), was conducted at four clinics with 594 women. Mean age and weight at admission were 25.5 years and 62.4 kg, respectively. Consent to continue through 5 years was sought and obtained when the 3-year cumulative pregnancy rate proved to be 0.8 per 100. No pregnancies occurred in the fourth or fifth years. The 5-year cumulative pregnancy rate was, therefore, 0.8 per 100 with an annual average pregnancy rate below 2 per 1000 women. Prolonged bleeding/spotting (8.2% of subjects) and irregular bleeding (5.6%) were the most frequently cited medical reasons for removal. Removals for headache (4.7%) and weight change (4.0%) were the next most frequent medical reasons. Between 1% and 2% of subjects during the 5-year trial sought removals for each of the following conditions: mood changes, lower abdominal pain, depression, or pain at the implant site. The mean annual continuation rate during the study was 77 per 100. Use per woman averaged 2.96 years. Mean removal time was 5.9 +/- 0.6 min. These data indicate that, for a 5-year period, the two LNG rod implants are equivalent to the six Norplant capsule implants with respect to safety and efficacy parameters, but permit easier and more rapid implant removal.

PIP: The newly developed 2-rod levonorgestrel (LNG) implant system has a surface area only 44% that of Norplant yet provides LNG release rates and blood levels similar to the 6-capsule Norplant system. Clinical trials of the 2-rod implant system initiated in 1990 demonstrated an exceptionally low cumulative pregnancy rate (0.8/100) in the first 3 years of use. This paper reports on an extension of the original study for an additional 2 years. 594 women at 4 study sites in the US and the Dominican Republic completed 5 years of method use. No pregnancies occurred in the fourth and fifth years of use. Thus, the 5-year cumulative pregnancy rate was 0.8/100, with an average annual pregnancy rate below 2/1000 women. The mean annual continuation rate during the 5-year study period was 77/100 women, with an average duration of use of 2.96 years. The most frequent reasons for medical removal were prolonged bleeding/spotting (8.2% of women), irregular bleeding (5.6%), headache (4.7%), and weight gain (4.0%). Mean removal time was 5.9 minutes and complications occurred in only 2.3% of removals. Overall, these findings confirm that the 2-rod LNG implant contraceptive has an effectiveness equivalent to the 6-capsule implant for a 5-year period, with good acceptability and a substantially improved ease of removal.

Contraception-associated menstrual problems: etiology and management.

PIP: Menstrual cycle irregularities are common during the first few months of use of hormonal contraception and the IUD. Although most contraception-related menstrual problems are not clinically significant, they can lead to erratic method use or even discontinuation. This article presents guidelines for the assessment and management of bleeding problems related to use of combined oral contraceptives (OCs), progestin-only pills, subdermal progestin implants, injections, and IUDs. Much of the patient dissatisfaction that results from these menstrual changes can be averted by careful counseling prior to method selection. Candid dialogue regarding the potential for bleeding disturbances is critical before a method is prescribed in order to avert the interrupted contraceptive practices that place women at risk of unintended pregnancy.^ieng

Medical abortion with oral methotrexate and vaginal misoprostol.

OBJECTIVE: To evaluate the safety and efficacy of oral methotrexate and vaginal misoprostol for medical abortion. METHODS: A prospective multicenter trial involved 300 women up to 49 days' gestation seeking elective abortion. Subjects received methotrexate 50 mg orally followed 5-6 days later by misoprostol 800 micrograms vaginally. The misoprostol dose was repeated if abortion did not occur. RESULTS: Complete abortion occurred in 273 of 299 women (91.3%; 95% confidence interval [CI] 87.5, 94.2%); one woman was lost to follow-up. Abortion occurred within 8 days of the methotrexate in 233 women (77.9%; 95% CI 72.8, 82.5%); the remaining 13.4% of women who aborted did so after a delay of 23.5 +/- 9.8 days (median 23 days, range 10-45). Vaginal bleeding lasted an average of 15 and 11 days in immediate and delayed-success abortions, respectively. Complete abortion rates decreased linearly with increasing body surface area. After methotrexate and misoprostol administration, nausea was reported in 37% and 33%, vomiting in 11% and 18%, diarrhea in 12% and 18%, and subjective fever or chills in 15% and 31% of subjects, respectively. CONCLUSION: Oral methotrexate followed by vaginal misoprostol is effective for abortion and represents an acceptable alternative to intramuscular methotrexate in regimens for medical abortion.

Levonorgestrel concentrations during use of levonorgestrel rod (LNG ROD) implants.

In a three-year randomized trial that included 398 women, blood samples were collected for the purpose of assaying levonorgestrel concentrations in women using a new two-rod contraceptive implant system or an earlier implant formulation, Norplant-2 implants. Sample collection was at 1, 3, 6, 9, and 12 months after placement and semiannually thereafter through three years. Resulting assays and analyses showed that levonorgestrel concentrations of each implant formulation decreased significantly with time after placement, with increasing body weight, and with ponderal index. In the third year, several measures indicated that concentrations of the contraceptive drug were higher in women using the LNG ROD implants than in users of the original formulation. No pregnancies occurred among women in either group in the three years. This study provides evidence that the minimum levonorgestrel concentration needed to protect against pregnancy is below 200 pg/ml, and possibly is below 175 pg/ml.

Serum concentrations of estradiol, progesterone, and levonorgestrel are not determinants of endometrial histology or abnormal bleeding in long-term Norplant implant users.

The objective of this study was to determine the relevance of serum estradiol, progesterone and levonorgestrel concentrations to endometrial histology and uterine bleeding associated with long-term Norplant implants use. Eighteen five-year users of Norplant implants had endometrial biopsies and determinations of serum estradiol, progesterone and levonorgestrel concentrations. Correlations among these factors and uterine bleeding were calculated. Proliferative endometrium (but not sex steroid levels) was associated with abnormal bleeding. Neither ovarian steroid nor levonorgestrel concentrations was a predictor of abnormal bleeding. Hyperplastic changes were not seen even with high estradiol and low levonorgestrel levels.

PIP: At the gynecologic clinic of San Francisco General Hospital in California, 18 women aged 27-44 who had used Norplant contraceptive implants for the full 5 years of effectiveness and who had at least 1 year of recurrent episodes of vaginal bleeding agreed to have an endometrial biopsy and a venipuncture for determination of serum estradiol, progesterone, and levonorgestrel levels. Investigators wanted to learn whether hormonal factors contributed to abnormal bleeding patterns in women who had used levonorgestrel-releasing contraceptive implants for 5 years. At the time of biopsy and venipuncture, 13 (72%) women had normal bleeding patterns. Two women had no apparent follicular activity. Six other women (44%) had a low estradiol level (i.e., 100 pg/ml). 14 women (77%) had no signs of luteal development (i.e., progesterone level 3 ng/ml). None of the women had hyperplastic endometrium. The endometrial index was used to describe endometrial histology and ranged from secretory to proliferated characteristics of the endometrium. It differed significantly between Norplant users with normal bleeding and those with abnormal bleeding (0.32 [a mixture of secretory and proliferative characteristics, but especially secretory characteristics] vs. 0.9 [close to full proliferation of the endometrium]; p 0.01). Serum estradiol, progesterone, and levonorgestrel levels were not significantly different between the two groups. These findings suggest that a proliferative endometrium, rather than sex steroid levels, was linked to abnormal bleeding. Thus, abnormal bleeding among long-term Norplant users is probably not a risk factor for developing endometrial cancer.

A randomized trial comparing misoprostol three and seven days after methotrexate for early abortion.

OBJECTIVE: Our purpose was to determine whether vaginal misoprostol 7 days rather than 3 days after methotrexate injection increases the percent of successful abortions on the day of misoprostol administration. STUDY DESIGN: A randomized controlled trial was performed in women requesting an abortion at < or = 56 days' gestation. Eighty-six women were treated with methotrexate 50 mg/m2 intramuscularly followed 3 days (group 1) or 7 days (group 2) later by vaginal misoprostol 800 micrograms. The misoprostol dose was repeated if the abortion did not occur. RESULTS: Complete abortion occurred in 38 of 46 (83%) patients in group 1 and 39 of 40 (98%) in group 2 (p = 0.033). Of the women with complete abortions, 30 of 46 (65%) in group 1 and 27 of 40 (68%) in group 2 aborted the same day as the first or second dose of misoprostol (p = 0.823). Vaginal bleeding lasted 14 +/- 5 (mean +/- SD) days in group 1 and 17 +/- 9 days in group 2. The remaining women aborted after a delay of 24 +/- 6 days in group 1 and 28 +/- 13 days in group 2. For these women vaginal bleeding lasted 18 +/- 17 and 14 +/- 7 days, respectively, and the human chorionic gonadotropin-beta level was < or = 25 IU/L by 22 +/- 7 days after the abortion in group 1 and 19 +/- 9 days in group 2. Treatment failures in group 1 were four continuing pregnancies (9%), two incomplete abortions (4%), and two women who requested surgical termination after receiving both medications (4%). The treatment failure in group 2 was an incomplete abortion. Methotrexate and misoprostol side effects were infrequent. CONCLUSIONS: Methotrexate and vaginal misoprostol are more effective abortifacients when the misoprostol is given 7 days rather than 3 days after methotrexate. This treatment regimen may offer an alternative to surgical abortion or the use of antiprogestins and prostaglandin for medical abortion.

Removal of levonorgestrel capsules from the biceps muscle.

Multiple levonorgestrel implants were identified and removed from below the biceps fascia using radiography to assist in localization, axillary block for anesthesia, careful dissection, and palpation of the implants within the deep muscle belly. This difficult implant removal demonstrates the importance of both a clinician experienced in levonorgestrel implant removal and a general surgeon experienced in arm surgery when performing such procedures.

Evaluation of a 1-year levonorgestrel-releasing contraceptive implant: side effects, release rates, and biodegradability.

OBJECTIVE: To determine the release rates, effects on ovulation, and side effects of two lengths of a biodegradable, subdermal contraceptive implant containing levonorgestrel in a caprolactone capsule. DESIGN: Phase II randomized clinical trial. SETTING: Public family planning clinic at an urban general hospital. PARTICIPANTS: Forty-eight healthy, parous, ovulating volunteers. INTERVENTION: Subjects were randomly assigned either a 2.5- or a 4.0-cm contraceptive capsule that was worn under the skin of the upper arm for 1 year if not removed earlier for other reasons. MAIN OUTCOME MEASURES: Serum concentrations of levonorgestrel, progesterone, estradiol, and lipoproteins were measured as were metabolic parameters. Vaginal bleeding and other side effects were recorded. After implant removal, remaining levonorgestrel, capsule viscosity, and molecular weight were measured. RESULTS: The 4-cm implant provided serum concentrations of levonorgestrel ranging from 0.65 ng/mL shortly after insertion to 0.20 ng/mL at 12 months, but the 2.5-cm implant resulted in levels too low for contraception. The 4-cm implant suppressed ovulation in approximately 80% of cycles over 1 year of use, but the 2.5-cm implant failed to suppress ovulation. The implants were rapidly and easily inserted and removed. They retained structural integrity through 1 year of use. Of 48 subjects, 32 had abnormal bleeding patterns; the mean number of days of bleeding per month was 7 with 23 days between episodes. Women using capronor maintained normal metabolic parameters except that low-density lipoprotein decreased slightly. CONCLUSIONS: The 4.0-cm implant is a promising contraceptive. There were no important metabolic effects, but there were bothersome minor side effects typical of progestin-only contraception.

Innovations in contraception: the Norplant system.

The Norplant (Huhtamaki Oy/Leiras Pharmaceuticals, Turku, Finland) contraceptive system is a safe, highly effective, reversible method of hormonal contraception. The system consists of six flexible match-size implants that are implanted in the inner aspect of the upper arm. This sustained-release system delivers the progestin levonorgestrel at levels sufficient to prevent pregnancy for as long as 5 years. Norplant is a convenient, easy-to-use method. Adequate counseling of potential users and appropriate selection of patient users are important determinants of patient satisfaction with Norplant.

PIP: The Norplant implant is described: the release rates and serum levels of levonorgestrel, the mode of action, the indications and contraindications, the effectiveness, incidence of ectopic pregnancy related to Norplant use, metabolic effects, advantages and disadvantages, insertion, the role of counseling, and management of side effects (menstrual bleeding changes, headache, weight changes, mastalgia, and acne), continuation rates and reasons for termination, and removal. Norplant is currently the most effective method of contraception. Counseling is important in order to provide women with as much information for informed consent and to increase awareness and interest in Norplant. In a clinical trial in California, 95% expressed a high level of satisfaction upon implant removal and 71% desired Norplant again; 91% recommended Norplant to friends. 82% reported the side effect of menstrual change; 66% reported 2 or more side effects. Clinical development is ongoing for other sustained release contraceptives. Norplant was developed by the International Committee for Contraceptive Research of the Population Council, and manufactured by Huhtamaki Oy/Leiras Pharmaceuticals in Turku, Finland. Clinical trials have been conducted since 1975. 20 nations have approved its use, and more than 1.5 million women use it. Silastic rubber tubing encapsulates 6 capsules of 36 mg/capsule crystalline levonorgestrel, a strong progestin. Implantation is done just under the skin in a fan shape; levonorgestrel is released at 80 mcg/day for 6 months, and 30-35 mcg/day for the remainder of use. The mode of action is not completely understood, but the assumption is that it is similar to the progestin-only pills. The mechanisms that alter fertility are 1) the change in hypothalamic-pituitary level to inhibit midcycle luteinizing hormone surge, while follicle stimulating hormone and estradiol levels remain within the normal range, 2) the thickening of the cervical mucus which prevents the entry of sperm into the upper genital tract, and 3) the suppression of the estrogen-induced cyclical maturation of the endometrium. It is not an abortifacient. Contraindications are few, but include active thrombophlebitis, undiagnosed abnormal genital bleeding, known or suspected pregnancy, benign or malignant liver tumors, and known or suspected breast cancer of progestin-dependent neoplasms.

Clinical evaluation of the Capronor contraceptive implant: preliminary report.

Capronor, a single-capsule, biodegradable, subdermal contraceptive that releases levonorgestrel over a 12- to 18-month period, has been evaluated in 48 healthy women, ages 18 to 40 years. Sixteen participants received a 2.5 cm capsule (12 mg of levonorgestrel), and 32 received a 4.0 cm capsule (21.6 mg of levonorgestrel). Serum levonorgestrel levels were significantly lower in the 2.5 cm group. Ovulation occurred in all cycles in the 2.5 cm group and in 26.3% of cycles in the 4.0 cm group. Levonorgestrel levels with the shorter capsule were too low for reliable contraception in all users, and 4 cm may be a minimal functional length. Bleeding patterns were regular in most women who ovulated and irregular in most remaining subjects. It is assumed that changes in cervical mucus and the endometrium contributed to effective contraception despite the frequency of ovulation.

PIP: Capronor, a single-capsule, biodegradable, subdermal contraceptive that releases levonorgestrel over a 12-18 month period, has been evaluated in 48 healthy women, ages 18 to 40 years. 16 participants received a 2.5 cm capsule (12 mg of levonorgestrel), and 32 received a 4.0 cm capsule (21.6 mg of levonorgestrel). Serum levonorgestrel levels were significantly lower in the 2.5 cm group. Ovulation occurred in all cycles in the 2.5 cm group and in 26.3% of cycles in the 4.0 cm group. Levonorgestrel levels with the shorter capsule were too low for reliable contraception in all users, and 4 cm may be a minimal functional length. Bleeding patterns were regular in most women who ovulated and irregular in most remaining subjects. It is assumed that changes in cervical mucus and the endometrium contributed to effective contraception despite the frequency of ovulation.

Prophylaxis in caesarean section with cefmetazole and cefoxitin.

A prospective, randomized, open comparison of three 1 g doses of cefmetazole with three 2 g doses of cefoxitin for non-elective Caesarean section was performed. Sixty-nine patients were evaluated. The two groups were comparable with respect to labour characteristics that might influence risk of postoperative infectious morbidity. Similarly, the nature of the bacterial contamination/infection of the amniotic fluid at the time of Caesarean section was comparable in the two groups. The only infectious morbidity noted was endomyometritis. The incidence was the same in both groups, 5/50 (10%) in the cefmetazole group and 2/19 (10.5%) in the cefoxitin group. Febrile morbidity, as reflected in the fever index, was not significantly different between the groups, 10.2 +/- 18.5 degree hours in the cefmetazole group and 7.5 +/- 11.7 degree hours in the cefoxitin group. Cefmetazole appeared to be equivalent to cefoxitin in reducing post-Caesarean section endomyometritis.