A fusion inhibitor prevents spread of immunodeficiency viruses, but not activation of virus-specific T cells, by dendritic cells.

Dendritic cells (DCs) play a key role in innate immune responses, and their interactions with T cells are critical for the induction of adaptive immunity. However, immunodeficiency viruses are efficiently captured by DCs and can be transmitted to and amplified in CD4(+) T cells, with potentially deleterious effects on the induction of immune responses. In DC-T-cell cocultures, contact with CD4(+), not CD8(+), T cells preferentially facilitated virus movement to and release at immature and mature DC-T-cell contact sites. This occurred within 5 min of DC-T-cell contact. While the fusion inhibitor T-1249 did not prevent virus capture by DCs or the release of viruses at the DC-T-cell contact points, it readily blocked virus transfer to and amplification in CD4(+) T cells. Higher doses of T-1249 were needed to block the more robust replication driven by mature DCs. Virus accumulated in DCs within T-1249-treated cocultures but these DCs were actually less infectious than DCs isolated from untreated cocultures. Importantly, T-1249 did not interfere with the stimulation of virus-specific CD4(+) and CD8(+) T-cell responses when present during virus-loading of DCs or for the time of the DC-T-cell coculture. These results provide clues to identifying strategies to prevent DC-driven virus amplification in CD4(+) T cells while maintaining virus-specific immunity, an objective critical in the development of microbicides and therapeutic vaccines.

CpG-C ISS-ODN activation of blood-derived B cells from healthy and chronic immunodeficiency virus-infected macaques.

Cytosine-phosphate-guanine class C (CpG-C) immunostimulatory sequence oligodeoxynucleotides (ISS-ODNs) activate human B cells and dendritic cells (DCs), properties that suggest potential use as a novel adjuvant to enhance vaccine efficacy. After demonstrating that the CpG-C ISS-ODN C274 activates macaque DCs, we examined in vitro activation of macaque B cells by C274 as a prelude to evaluation of this molecule as an adjuvant in the testing of candidate human immunodeficiency virus vaccines in the rhesus macaque-simian immunodeficiency virus (SIV) model. C274 induced macaque CD20(+) B cells to proliferate more strongly than CD40 ligand or CpG-B ISS-ODN. C274 enhanced B cell survival; increased viability was most evident after 3-7 days of culture. Increased expression of CD40, CD80, and CD86 by B cells was apparent within 24 h of exposure to C274 and persisted for up to 1 week. C274-stimulated, B cell-enriched and peripheral blood mononuclear cell suspensions from naïve and immunodeficiency virus-infected monkeys secreted several cytokines [e.g., interleukin (IL)-3, IL-6, IL-12, interferon-alpha] and chemokines [e.g., monocyte chemoattractant protein-1/CC chemokine ligand 2 (CCL2), macrophage-inflammatory protein-1alpha/CCL3, IL-8/CXC chemokine ligand 8]. In comparison, exposure of macaque B cells to SIV had minimal impact on surface phenotype, despite inducing cytokine and chemokine production in cells from infected and uninfected animals. These observations emphasize the need to identify strategies to optimally boost immune function, as immunodeficiency viruses themselves only partially activate B cells and DCs. The ability of C274 to stimulate B cells and DCs in healthy and infected monkeys suggests its possible use as a broad-acting adjuvant to be applied in the rhesus macaque model for the development of preventative and therapeutic vaccines.

Immediate postabortal contraception with the levonorgestrel intrauterine device, Norplant, and traditional methods.

Women seeking legal first trimester abortion were counseled concerning contraception methods available for use immediately postabortion. Fifty women each accepted hormonal methods that were available only in the clinic and were novel to the country, the levonorgestrel IUD and Norplant implants, whereas another 50 chose either coitus interruptus or abstinence. All were experienced contraceptors, but larger percentages of women selecting the levonorgestrel IUD or implants had used the pill or IUDs previously, were under age 30, and weighed less than 60 kg compared to the other study participants. In the initial 2-6 weeks postabortion, women using the long-acting hormonal methods resumed sexual activity earlier and experienced more bleeding and spotting days than did other study participants, but their hematocrits were not adversely affected. No clinically significant side effects were noted in any group in the 6 weeks following the abortion. At the end of 1 year of follow-up, women using the hormonal methods had experienced no pregnancies and had high rates of continuation. IUD and implant participants had greater weight gain than did the other participants, but their mean weight remained below that of participants using traditional methods. No significant between-group differences in levels or changes in levels from admission were noted in hematocrit and blood pressure. The women found the levonorgestrel implants and IUDs easy and safe to use and highly effective. Bleeding disturbances, including amenorrhea, were the principal features the women disliked.

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.

Safety and efficacy of levonorgestrel implant, intrauterine device, and sterilization.

OBJECTIVE: To evaluate safety and efficacy of levonorgestrel-releasing contraceptive implants (Norplant; Leiras Oy, Turku, Finland) in developing countries. METHODS: We used controlled cohort methodology. Women attending family planning clinics in eight developing countries selecting Norplant were enrolled, together with women of similar age choosing intrauterine devices (IUDs) or surgical sterilization. Participants were interviewed and examined at semi-annual visits and followed-up for 5 years regardless of change of contraceptive methods. Incidence rate ratios of health events were estimated for initial and current method use. RESULTS: Altogether, 7977 women initiated Norplant, 6625 IUD, and 1419 sterilization. The overall follow-up rate was 94.6% and 78,323 woman-years of observation were accumulated. Pregnancy rates for Norplant, copper IUDs, and sterilization each averaged less than 1 per 100 woman-years. With two exceptions, no significant excess risk of serious morbidity was detected for Norplant users compared with controls. The incidence of gallbladder disease was higher in women who initiated Norplant use than in controls (rate ratio 1.52, 95% confidence interval [CI] 1.02, 2.27), as was the incidence of hypertension and borderline hypertension in current implant users (rate ratio 1.81; CI 1.12, 2.92). Other new findings were increased risks of respiratory diseases and decreased risks of inflammatory disease of the genital tract in Norplant users compared with IUD users and sterilized women. CONCLUSION: The study confirms the safety with respect to serious disease and the high contraceptive efficacy of Norplant, copper 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.

Levonorgestrel capsule implants in the United States: a 5-year study.

OBJECTIVE: To measure effectiveness, adverse event experience, and acceptability of the Food and Drug Administration-approved variant of levonorgestrel capsule implants in the United States through 5 years and to examine determinants of these outcomes. METHODS: In a prospective, multicenter study, 511 sexually active women selecting contraceptive implants were monitored four times in the 1st year, then semiannually through 5 years. Adverse events were elicited by query and physical examination, and their incidence was measured. Lifetable analyses computed pregnancy and other discontinuation rates. Cox regression models examined effects of age, parity, and preadmission desire for more children on continuation. Removal times were analyzed by analysis of variance. RESULTS: Three pregnancies occurred, yielding a 5-year cumulative rate of 1.3+/-0.8 per 100 users, an average annual rate of three per 1000 women, and an ectopic pregnancy rate of 0.6 per 1000 woman years. No pregnancies occurred to women weighing less than 79 kg. Prolonged or irregular menstrual bleeding, followed distantly by headache, weight gain, and mood changes, was the most frequent medical conditions leading to removal. Weight gain averaged 1 kg per year. Each annual continuation rate was above 80 per 100, for a cumulative 5-year rate of 39 per 100. Continuation was age-dependent, with younger women (younger than 25 years at entry) having lower 5-year continuation rates than older subjects (P < .01). Tissue trauma from deeply placed or poorly aligned implants or severe reactions to local anesthetic affected subjects in 3.1% of removals (nine cases). CONCLUSION: As measured by annual continuation rates of 80 per 100 or higher and annual pregnancy rates below one per 100, implant contraception in the United States was found to be highly acceptable and effective, year after year, regardless of the woman's age or family formation status. The cumulative 5-year pregnancy rate, 1.3 per 100, is comparable to that of tubal ligation.

Acceptability and feasibility of early pregnancy termination by mifepristone-misoprostol. Results of a large multicenter trial in the United States. Mifepristone Clinical Trials Group.

OBJECTIVES: To evaluate whether the regimen of oral mifepristone and misoprostol for medical abortion is acceptable to women and providers, in the United States, including physicians, nurses, and counselors, and whether proposed modifications of this regimen appear feasible for clinical practice. DESIGN: A prospective study. SETTING: Seventeen clinics in 15 states. PARTICIPANTS: A total of 2121 women with pregnancies of 63 days or less in duration. INTERVENTIONS: The administration of mifepristone, 600 mg, orally, followed after 2 days by the administration of misoprostol, 400 micrograms, orally. Clinical observation for 4 hours followed misoprostol administration. Two weeks later, at a checkup, women were questioned about the abortion experience. Providers also answered questions about acceptability and feasibility. MAIN OUTCOME MEASURES: Patient reports of overall satisfaction with the abortion, the number of women who would choose medical abortion again if needed or recommend the method to others, the best and worst features of the method, and provider and patient assessments of home use. RESULTS: The regimen was highly acceptable. Nearly all women (95.7%) would recommend it to others, 91.2% would choose it again, and 87.6% found it very or moderately satisfactory. Even among women for whom the method failed, 69.6% would try it again, 84.9% would recommend it to others, and 51.9% found it very or moderately satisfactory. The chance to avoid a surgical procedure was reported as the method's best feature. The most commonly cited worst features were the uncertainty and fear of side effects. Providers and women considered home use feasible and safe. CONCLUSIONS: American women found abortion with the use of mifepristone and misoprostol acceptable. Even most with unsuccessful outcomes would select the regimen again and recommend it to others. Most providers and women thought that home use of misoprostol should be available for women who prefer it.

Norplant consensus statement and background review.

This review has highlighted the attributes of a very important new method of contraception. The signatories to this document agree that, with the provision of appropriate information and instruction for the user, Norplant is a good contraceptive choice to be made available worldwide in family planning programs that have the resources for appropriate training and counseling. The signatories to this document are acting in their own personal capacity and not as representatives of any particular organization.

PIP: The Norplant contraceptive implant has been registered in 60 countries and used by over 6 million women worldwide. Clinical studies have repeatedly confirmed this method's long-term efficacy and safety when used appropriately. Preliminary findings of the Post-Marketing Surveillance study of Norplant, a 5-year prospective study conducted in 32 family planning clinics in 8 developing countries in 1987-97, indicate an intrauterine pregnancy rate of 0.23/100 woman-years, an ectopic pregnancy rate of 0.03/100 woman-years, and a 67.3% continuation rate at 5 years. No significant excess of malignant neoplastic or cardiovascular disease has been observed. The major side effect is an irregular pattern of uterine bleeding, associated with about 25% of the discontinuations after 5 years of use. The quality of the family planning service is a major determinant of successful Norplant use and the degree of user satisfaction. Informed choice, the quality of follow-up care, easy access to removal services, and provider skills and attitudes are also critical. The signatories to this Consensus Statement (acting as individuals rather than representatives of their organizations) agree that, with the provision of appropriate information to users, Norplant is a good contraceptive choice that should be made available globally in all family planning programs with resources for appropriate training and counseling.

The performance of levonorgestrel rod and Norplant contraceptive implants: a 5 year randomized study.

A new contraceptive (LNG rod implants, Jadelle, Leiras Oy's registered trademark for rod implants) was prospectively evaluated in randomized 5 year comparison with Norplant (Population Council's registered trademark for contraceptive implants releasing levonorgestrel) capsule implants. The study involved 1198 women at seven centres. No pregnancies occurred in the first 4 years. At 5 years, the cumulative pregnancy rate was 1 per 100 users or less for each regimen. Annual discontinuation rates averaged 11-12 per 100 users (P > 0.05), corresponding to 5 year continuation rates of 55.1 for rods and 53.0 per 100 for capsules. Mean annual discontinuation rates for menstrual disturbances were 3.5 and 4.2 per 100 for rod and capsule implants respectively (P > 0.05), and mean annual removal rates for medical problems were 3.5 and 3.0 per 100 (P > 0.05) respectively. Apart from menstrual problems, headache, weight gain and acne were the principal medical reasons for removal. In proportional hazard analyses, family formation variables, age, parity and desire/non desire for another child, recorded at admission, significantly affected discontinuation rates for major decrement categories and for all reasons combined. Mean rod removal time was half that of Norplant (P < 0.01); complications of rod removal were at a lower rate. With these contraceptives indistinguishable in performance except for ease and speed of removal, LNG rod implants appear to be preferable to Norplant for use through 5 years by virtue of relative ease of removal.

PIP: This paper presents the 5-year randomized study on the performance of levonorgestrel rod (LNG) and Norplant contraceptive implants in 1198 women in 7 centers. In the first 4 years, no pregnancies occurred. At 5 years, the cumulative pregnancy rate was 1/100 users or less for each regimen. Annual discontinuation rates averaged 11-12/100 users, corresponding to a 5-year continuation rate of 55.1/100 for rods and 53.0/100 for capsules. Mean annual discontinuation rates for menstrual disturbances were 3.5/100 for rod and 4.2/100 for capsule implants. Reasons for discontinuation of use were vaginal spotting or bleeding, irregular bleeding, headache, weight gain and acne. Proportional hazard regression models established that family formation variables, age, parity, and desire for another child, recorded at admission, significantly affected discontinuation rates for major decrement categories and for all reasons combined. Mean rod removal time was half that of Norplant. Complications of rod removal were at a lower rate. This study concludes that there is an extremely high contraceptive effectiveness for LNG rod and Norplant implants; however, LNG rod implants were more preferable than Norplant for its relative ease in removal.

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.

Contraceptives for lactating women: a comparative trial of a progesterone-releasing vaginal ring and the copper T 380A IUD.

From approximately one week before normal ovulation resumes, lactating women require protection against pregnancy by a contraceptive that is safe for both infant and mother in a multicenter one-year study, the natural hormone, progesterone, delivered vaginally by a sequence of four contraceptive rings designed for continuous use, was evaluated as a contraceptive for nursing mothers in comparison with the Copper T 380A IUD. Individual rings release in effective average dose of 10 mg day for a 3 month period. Evaluation included measures of lactational performance as well as of contraceptive efficacy and safety to mother and child. Nine participating clinics enrolled 802 ring users and 734 IUD acceptors between postpartum days 29 and 63. Life table analyses were performed with parallel decrements for ring and IUD subjects. Continuation in the study and analysis required that subjects not stop breastfeeding. The ring, with a one-year pregnancy rate of 1.5 per 100, did not differ significantly from the IUD with respect to contraceptive effectiveness (p > 0.05). More than half of the ring subjects were continuing at 6 months post admission and a quarter (23.5 per hundred) were still using the ring and breastfeeding one year after admission. Women with the IUD, however, had higher continuation rates (p < 0.001) at both time points. The largest single decrement for each method was that for weaning. Ring users had more complaints of vaginal problems but had fewer vaginal disorders on examination. At 12 months postpartum, 46 per 100 continuing ring users remained in amenorrhea. Lactation performance and the health and weight gain of the infants were similar among users of either regimen.

PIP: A multicenter trial conducted in nine clinics in Asia, Latin America, North Africa, and the US indicated the progesterone-releasing vaginal ring (PVR) is a safe, effective contraceptive method for lactating women. Study participants, enrolled 4-9 weeks postpartum, agreed to fully or nearly fully breast feed for at least 3 months after admission. The ring released an average of 10 mg of progesterone per day for a 3-month period. The Copper T 380A IUD served as the non-hormonal control. A total of 431 and 533 woman-years of observation were accumulated in the PVR and IUD groups, respectively. After 12 months of use, the cumulative pregnancy rate was 1.5 per 100 in the PVR group and 0.5 per 100 in the IUD group. In the year following admission, 3.4% of PVR acceptors complained of heavy and/or prolonged bleeding. At 12 months postpartum, 46.2% of ring users compared with only one-sixth of IUD users remained amenorrheic. Although PVR acceptors reported more vaginal problems (e.g., discharge or leukorrhea), pelvic examinations were more likely to detect abnormalities in IUD users. The 6- and 12-month continuation rates were 52.5% and 23.5%, respectively, in the PVR group and 74.8% and 34.5%, respectively, in the IUD group. The predominant reason for discontinuation was weaning. Breast feeding performance and infant growth were within normal limits for the PVR and IUD. Both methods are highly effective and appropriate for use by lactating women from the second postpartum month forward; the PVR has the additional advantage of being user-controlled.

Safety, efficacy, and acceptability of medical abortion in China, Cuba, and India: a comparative trial of mifepristone-misoprostol versus surgical abortion.

OBJECTIVE: We investigated safety, efficacy, and acceptability of an oral regimen of medical abortion compared with surgical abortion in three developing countries. STUDY DESIGN: Women (n = 1373) with amenorrhea < or = 56 days chose either surgical abortion (as provided routinely) or 600 mg of mifepristone followed after 48 hours by 400 micrograms of misoprostol. This is the appropriate design for studying safety, efficacy, and acceptability among women selecting medical abortion over available surgical services. RESULTS: The medical regimen had more side effects, particularly bleeding, than did surgical abortion but very few serious side effects. Failure rates for medical abortion, although low, exceeded those for surgical abortion: 8.6% versus 0.4% (China), 16.0% versus 4.0% (Cuba), and 5.2% versus 0% (India). Nearly half of failures among medical clients were not true drug failures, however, but surgical interventions not medically necessary (acceptability failures or misdiagnoses). Women were satisfied with either method, but more preferred medical abortion. CONCLUSION: Medical abortion can be safe, efficacious, and acceptable in developing countries.

PIP: A multi-center comparative study of medical compared to surgical abortion confirmed that medical abortion can be safe, effective, and acceptable in developing countries. A total of 1373 women from medical centers in China, Cuba, and India with pregnancies of 56 days' gestation or less were given the choice of surgical abortion or 600 mg of mifepristone followed after 48 hours by 400 mcg of misoprostol. Since the majority selected medical abortion, researchers in China and Cuba assigned some of these women to the surgical group to equalize the size of the two groups. The surgical abortion failure rates in China, Cuba, and India were 0.4%, 4%, and 0%, respectively, while the failure rates for medical abortion were 8.6%, 16.0%, and 5.2%, respectively. In all sites, both medical failures (an adverse effect resulting in a medically indicated surgical intervention) and acceptability failures (failure to complete the entire regimen) contributed substantially to the gross failure rates for medical abortion. Medical abortion failure rates increased with gestational age. Although cramping, nausea, and vomiting were more frequent among women in the medical abortion group and bleeding was heavier, general assessments of well-being reported at exit interviews did not differ between the two treatment groups at any site. Regardless of abortion method, the majority of women were either satisfied or highly satisfied with the procedure. In all countries, a higher number of medical than surgical abortion patients indicated they would opt again for the same procedure. Neither the bleeding pattern nor the higher failure rate associated with medical abortion justify withholding this option from women in developing countries.

Clinical performance of a new two-rod levonorgestrel contraceptive implant: a three-year randomized study with Norplant implants as controls.

In a randomized three-year clinical trial at seven clinics, the performance of levonorgestrel rod (LNG ROD) implants used by 600 women was compared with that of soft tubing NORPLANT implants used by 598 women. No pregnancies occurred in either group of women and, accordingly, body weight did not affect the efficacy of either type of implant. There were neither statistically significant nor important differences in termination rates for any reason over the three years. Complaint and illness rates during use of either of the two implant types were statistically indistinguishable and were attributable to the same set of conditions. Seventy-one per 100 of the women using each implant regimen continued to the three-year point, for an average annual continuation rate of 89 per 100. Removals of LNG ROD implants were accomplished in about half the time required for removal of Norplant capsule implants (p < 0.001).

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.

First week drug concentrations in women with levonorgestrel rod or Norplant capsule implants.

Forty-two healthy women volunteered to have blood samples drawn at 2, 4, 8, 24, 48, and 168 h (7 days) following placement of levonorgestrel-releasing rod (LNG rod) or of Norplant capsule implants to permit measurement of drug concentrations. Three clinics recruited 10 women each, half of whom used each type of implant. Twelve additional subjects were later enrolled at one site to provide greater detail for the capsule implants. Throughout the week, women with Norplant implants had apparently higher mean drug concentrations than did women with LNG rod implants, but the differences were significant only in the first 48 h after placement (p < 0.05). Maximum levels for capsule implants were found at the 24-h sample (mean, 1358 to 1474 pg/mL) and for the LNG rod implants at 48 h (772 pg/mL). Body weight was negatively correlated with levonorgestrel concentrations at all times (p < 0.05). For several sampling times, differences between clinics in mean concentrations were statistically significant after weight adjustment. Despite differences by implant type, weight, or clinic location, drug concentrations compatible with contraceptive effect were attained within 24 h in users of LNG rod or of Norplant implants, insofar as all women had levonorgestrel concentrations above 250 pg/mL at the 24-h sample.

PIP: To establish the minimum times required for contraceptive implants to achieve serum concentrations compatible with contraceptive action, drug concentrations were measured in blood samples collected from 42 women at 2, 4, 8, 24, and 168 hours after implant insertion. 15 volunteers from three centers (US, Chile, and the Dominican Republic) were fitted with a levonorgestrel (LNG)-releasing rod and 27 received Norplant implants. An LNG concentration of 250 pg/ml and above was considered indicative of contraceptive action. By 8 hours, all Norplant subjects but only 40% of the LNG rod subjects had achieved this serum level. By 24 hours, however, all women in both groups had LNG concentrations above 250 pg/ml. The maximum mean LNG level was recorded in the 24-hour sample (1358 pg/ml) in the Norplant group and at 48 hours (772 pg/ml) in the LNG rod group. Consistent with earlier investigations, LNG concentrations demonstrated strong and significant negative correlations with body weight at all time points. The paucity of pregnancies recorded in large-scale clinical trials in the first month of use of contraceptive implants supports the rapid attainment of effective LNG concentrations. It remains unclear, however, precisely how late in the menstrual cycle implants can be inserted and still prevent follicular development or halt ovulation. Until more information is available, continuation of the policy of implant placement in the first few days after the onset of menstruation is recommended.

Immediate postplacental insertion of GYNE-T 380 and GYNE-T 380 postpartum intrauterine contraceptive devices: randomized study.

OBJECTIVE: The purpose of the investigation was to compare the 1-year expulsion and efficacy rates of the GYNE-T 380 and the GYNE-T 380 Postpartum intrauterine contraceptive devices when inserted within 10 minutes after expulsion of the placenta in a term pregnancy. The two intrauterine contraceptive devices were identical, except that one was inserted by means of a temporary fundal suspension system and the other was placed directly into the uterine cavity. STUDY DESIGN: The study was a multicenter, randomized trial of intrauterine contraceptive devices in which 300 subjects accepted the GYNE-T 380 IUD and 292 subjects the GYNE-T 380 Postpartum IUD in clinics with adequate follow-up. RESULTS: At 1 year the gross cumulative expulsion rate was 13.2 per 100 cases (39 expulsions) with the GYNE-T 380 intrauterine contraceptive device and 16.2 per 100 cases (46 expulsions) with the GYNE-T 380 Postpartum device. There was no significant difference in the rate of expulsion between the two devices at any time during the year. There was one first-year intrauterine pregnancy, which occurred in a subject using the GYNE-T 380 device. The continuation rate for each device was above 80 per 100. CONCLUSION: The results indicate that both the GYNE-T 380 Postpartum and the standard GYNE-T 380 intrauterine contraceptive devices are safe and effective when inserted immediately after delivery of the placenta.

PIP: In clinics in Belgium, Chile, and the Philippines, data on 300 healthy, sexually active acceptors of the GYNE- T 380 IUD were compared with data on 292 healthy, sexually active acceptors of the GYNE-T 380 Postpartum IUD in order to compare the 10-year expulsion and efficacy rates of these 2 IUDs when inserted within 10 minutes of delivery of the placenta in a term pregnancy. The IUDs were identical, except that the GYNE-T 380 Postpartum IUD was inserted by a temporary fundal suspension system, while the GYNE-T 380 IUD was inserted directly into the uterus. No perforations occurred. The minimal complications that did occur were the same as those associated with interval IUD insertion: irregular spotting, menorrhagia, and uterine cramping. The rates for IUD discontinuation due to bleeding or pain and for other medical reasons were the same for both copper- releasing IUDs (3%). The removal rate for other medical reasons was less than 1% for each IUD. The only intrauterine pregnancy occurred in a woman using the nonsuspended, standard GYNE-T 380 IUD. The IUD continuation rate was greater than 80% for each IUD. Within each clinic, no statistically significant difference in the IUD expulsion rate existed at any time during the 12-month study period. Overall, the expulsion rates for the 2 IUDs were similar (e.g., at 12 months, 16.2% for GYNE-T 380 Postpartum IUD and 13.2% for GYNE-T 380 IUD). The Philippine clinic had significantly higher 1-year IUD expulsion rates regardless of IUD type than the Chilean clinic (24-32% vs. 5-6%). The Belgian clinic had moderately high 1-year IUD expulsion rates regardless of IUD type (8-16%). The different expulsion rates between clinics suggest differences in techniques used during insertion. These findings show that both IUD types inserted immediately after placental delivery are safe and acceptable. If the techniques associated with the low expulsion rates in Chile can be taught, these IUDs can be a practical, safe, convenient, and acceptable contraceptive method.