Misoprostol dose and route after mifepristone for early medical abortion: a randomised controlled noninferiority trial.

OBJECTIVE: To compare 400 and 800 microg sublingual or vaginal misoprostol 24 hours after 200 mg mifepristone for noninferiority regarding efficacy in achieving complete abortion for pregnancy termination up to 63 days of gestation. DESIGN: Placebo-controlled, randomised, noninferiority factorial trial, stratified by centre and length of gestation. Misoprostol 400 or 800 microg, administered either sublingually or vaginally, with follow up after 2 and 6 weeks. SETTING: Fifteen obstetrics/gynaecology departments in ten countries. POPULATION: Pregnant women (n = 3005) up to 63 days of gestation requesting medical abortion. METHODS: Two-sided 95% CI for differences in failure of complete abortion and continuing pregnancy, with a 3% noninferiority margin, were calculated. Proportions of women with adverse effects were recorded. OUTCOME MEASURES: Complete abortion without surgical intervention (main); continuing live pregnancies, induction-to-abortion interval, adverse effects, women's perceptions (secondary). RESULTS: Efficacy outcomes analysed for 2962 women (98.6%): 90.5% had complete abortion after 400 microg misoprostol, 94.2% after 800 microg. Noninferiority of 400 microg misoprostol was not demonstrated for failure of complete abortion (difference: 3.7%; 95% CI 1.8-5.6%). The 400-microg dose showed higher risk of incomplete abortion (P < 0.01) and continuing pregnancy (P < 0.01) than 800 microg. Vaginal and sublingual routes had similar risks of failure to achieve complete abortion (P = 0.47, difference in sublingual minus vaginal -0.7%, 95% CI -2.6-1.2%). A similar pattern was observed for continuing pregnancies (P = 0.21). Fewer women reported adverse effects with vaginal than sublingual administration and with the 400-microg dose than the 800-microg dose. Of the women, 94% were satisfied or highly satisfied with the regimens, 53% preferred the sublingual route and 47% preferred the vaginal route. CONCLUSIONS: A 400-microg dose of misoprostol should not replace the 800-microg dose when administered 24 hours after 200 mg mifepristone for inducing abortion in pregnancies up to 63 days. Sublingual and vaginal misoprostol have similar efficacy, but vaginal administration is associated with a lower frequency of adverse effects.

Two mifepristone doses and two intervals of misoprostol administration for termination of early pregnancy: a randomised factorial controlled equivalence trial.

OBJECTIVE: To compare the efficacy of 100 mg and 200 mg of mifepristone and 24- and 48-hour intervals to administration of 800 microg vaginal misoprostol for termination of early pregnancy. DESIGN: Placebo-controlled, randomized, equivalence trial, stratified by centre. SETTING: 13 departments of obstetrics and gynecology in nine countries. POPULATION: 2,181 women with 63 days or less gestation requesting medical abortion. METHODS: Two-sided 95% CI for the risk differences of failure to complete abortion were calculated and compared with 5% equivalence margin between two doses of mifepristone and two intervals to misoprostol administration. Proportions of women with adverse effects were compared between the regimens using standard testes for proportions. OUTCOME MEASURES: Rates of complete abortion without surgical intervention and adverse effects associated with the regimens. RESULTS: Efficacy outcome was analysed for 2,126 women (97.5%) excluding 55 lost to follow up. Both mifepristone doses were found to be similar in efficacy. The rate of complete abortion was 92.0% for women assigned 100 mg of mifepristone and 93.2% for women assigned 200 mg of mifepristone (difference 1.2%, 95% CI: -1.0 to 3.5). Equivalence was also evident for the two intervals of administration: the rate of complete abortion was 93.5% for 24-hour interval and 91.7% for the 48-hour interval (difference -1.8%, 95% CI: -4.0 to 0.5). Interaction between doses and interval to misoprostol administration was not significant (P = 0.92). Adverse effects related to treatments did not differ between the groups. CONCLUSIONS: Both the 100 and 200 mg doses of mifepristone and the 24- and 48-hour intervals have a similar efficacy to achieve complete abortion in early pregnancy when mifepristone is followed by 800 micrograms of vaginally administered misoprostol.

Factors in nonuniform induction of azoospermia by testosterone enanthate in normal men. World Health Organization Task Force on Methods for the Regulation of Male Fertility.

OBJECTIVE: To identify factors differentiating men becoming azoospermic from those remaining oligozoospermic within 6 months of T treatment. DESIGN: Prospective, open, noncomparative contraceptive efficacy study. SETTING: International multicenter study of 271 men in 10 centers in seven countries. PATIENTS: Data from 157 achieving azoospermia and 68 remaining oligozoospermic after 6 months of treatment were analyzed. The remaining 46 men were excluded as having unclassifiable suppression status due to discontinuation before completion of suppression. INTERVENTIONS: Weekly IM injections of 200 mg T enanthate. MAIN OUTCOME MEASURES: Anthropometric, seminal, hormonal, and biochemical data obtained before, during, and after treatment as potential predictors of consistent azoospermia. RESULTS: Azoospermic men had [1] faster rates of fall in sperm output and, after a delay of 75 +/- 4 days (mean +/- SE) for sperm to reappear in the ejaculate, exhibited a faster rate of recovery of sperm output; [2] higher pretreatment levels of FSH (mean +/- SE; 3.7 +/- 0.3 versus 2.7 +/- 0.4 mIU/mL [conversion factor to SI units, 1.00]); and [3] (if treated for > 15 months) a prolonged after treatment rebound in gonadotropins compared with nonazoospermic men. There were no other differences in pretreatment variables or plasma T levels and changes in androgen-sensitive markers during treatment. None of the variables explained the higher rates of azoospermia among men in Chinese (91%, n = 3) compared with non-Chinese centers (60%, n = 7). CONCLUSION: Nonuniformity of T-induced azoospermia among healthy fertile men is not due to anthropometric or ethnic differences, to variations in androgen effects, or to poor compliance with treatment. The heterogeneity in individual susceptibility to T-induced azoospermia is most consistent with quantitative differences in the hormonal regulation of spermatogenesis and is likely to be evident with other hormonal methods for male contraception.

Effects of testosterone enanthate in normal men: experience from a multicenter contraceptive efficacy study. World Health Organization Task Force on Methods for the Regulation of Male Fertility.

OBJECTIVE: To evaluate the secondary impact of a prototype androgen contraceptive regimen on physical, metabolic and behavioral variables. DESIGN: Prospective, open, noncomparative contraceptive efficacy study. SETTING: International multicenter study comprising 10 centers in seven countries. SUBJECTS: Two hundred seventy-one healthy men, age 31.8 +/- 5.4 years (mean +/- SD), range 21 to 45 years. INTERVENTIONS: Weekly IM injections of 200 mg T enanthate. MAIN OUTCOME MEASURES: Adverse effects and discontinuations; biochemical and hematologic changes and interpopulation differences. RESULTS: Chinese subjects were shorter and lighter and their baseline hemoglobin, plasma lipid, and liver enzyme levels were lower than in non-Chinese subjects. The most common side effects were painful injections, acne, fatigue, and weight gain. Gynecomastia and prostate problems were detected in 24 and 9 men, respectively, though no men stopped injections for such reasons. Testosterone enanthate increased body weight, hemoglobin, and urea but decreased testicular volume and creatinine. Plasma triglyceride, cholesterol, and low-density lipoprotein cholesterol were unchanged; high-density lipoprotein cholesterol decreased by 14% to 18% in non-Chinese but was unchanged in Chinese men. Liver transaminases were increased by 36% to 51% in Chinese but were unchanged in non-Chinese subjects. These T enanthate-induced effects were reversible within 6 months of stopping injections and were not related to the duration of T exposure. CONCLUSIONS: Testosterone enanthate administration in a contraceptive trial produced significant but reversible effects on skin, muscle, liver, lipid metabolism, and hemopoietic functions that varied between population groups. These effects reflect the relatively high peak levels and fluctuations of plasma T produced by the weekly T enanthate regimen rather than an inherent feature of hormonal male contraception. The results highlight the need for long-acting preparations of T with more stable delivery kinetics.

PIP: At 10 centers in 7 countries, researchers conducted a clinical trial of weekly intramuscular injections of 200 mg testosterone (T) enanthate in 271 healthy fertile men, 21-45 years old, to evaluate the secondary impact of this prototype male contraceptive regimen on various physical, metabolic, and behavioral variables. They also focused on the differences between Chinese men and non-Chinese men as well as their similarities. At baseline, Chinese men were shorter, weighed less, and had lower levels of hemoglobin, plasma lipids, and liver enzymes than non-Chinese men (p 0.05). The overall leading side effects were acne (80), fatigue (22), painful injections (15), and weight gain (12). 24 men, all of whom were non-Chinese men, experienced excessive development of the male mammary glands (gynecomastia). Nine men (1 Chinese, 8 non-Chinese) had prostate problems. No man discontinued T enanthate injections for gynecomastia or prostate problems, however. T enanthate contributed to an increased body weight (by 5% at 360 days) and increased levels of hemoglobin (by 7.6% at 360 days) and creatinine while it contributed to a decrease in testicular volume (by 26.2% at 360 days) and in urea level. T enanthate appeared to have no effect on plasma triglyceride, cholesterol, and low density lipoprotein (HDL) cholesterol. It was associated with a decrease of 14-18% in HDL-cholesterol in non-Chinese men but it had no effect on HDL-cholesterol in Chinese men. T enanthate increased liver transaminase by 36-51% in Chinese men but it had no effect on these enzymes in non-Chinese men. Regardless of length of exposure to T enanthate, the T enanthate-induced changes were reversible within 6 months. These findings suggest that T enanthate produced significant but reversible metabolic and physical effects that differed between Chinese and non-Chinese men. These effects are a result of the relatively high peak levels and fluctuations of plasma T produced by the weekly injections rather than an inherent feature of hormonal male contraception.

Assessing the acceptability, service delivery requirements, and use-effectiveness of the diaphragm in Colombia, Philippines, and Turkey.

The diaphragm is not available in many countries, despite the recommendations of numerous authors that it has important advantages as a woman-controlled method that offers some protection against sexually transmitted diseases, and one that is safe and free of side effects. An interagency team collaborated to introduce the diaphragm in Colombia, the Philippines, and Turkey, using the same protocol to assess the acceptability, service delivery requirements and use-effectiveness of the method. Eighteen public and private sector service delivery sites were involved and a total of 550 women were enrolled in the study. Provider training aimed to improve the quality of care with which all methods were delivered and included counseling about sexuality and reproductive health risks. The cumulative 12-month pregnancy rate of 10.1 (SE 1.7) per 100 woman-years is on the low end of previous studies of the diaphragm, and the 12-month continuation rate (57.2 [SE 2.4] per 100) compares favorably with that for oral contraceptives and the intrauterine device. Focus group discussions conducted with clients and providers indicated that the method was an important alternative for some women, particularly those who had experienced health problems with other methods or were unable to negotiate condom use with their partners. Provider biases diminished as they observed the strategic niche that the diaphragm filled for their clients. While providing the diaphragm requires training and good client-provider interaction, the requirements are consistent with those called for in the Programme of Action of the International Conference on Population and Development (ICPD, 1994). With proper attention to quality of care, the diaphragm can be successfully offered in resource-poor settings.

A competing risk approach to the analysis of trials of alternative intra-uterine devices (IUDs) for fertility regulation.

The methods of survival analysis have had a profound influence on the way that studies concerned with the safety and efficacy of intra-uterine devices (IUDs) for fertility control have been designed, conducted, analysed and reported. For example, the Kaplan-Meier technique has been used to summarize the results of controlled clinical trials of alternative devices and the logrank test used to make any comparisons. A particular feature of IUD studies is the large number of possible causes of failure (reasons for discontinuation of the device). These lead to considerations of competing risks, where in this framework, the discontinuations are considered as competing causes of contraceptive failure. In this context, we compare the net and crude probability estimates of discontinuation rates using continuous time and argue for the routine use of the latter. We use data from a randomized multi-centre trialon the long-term safety and efficacy of two IUDs, TCu220C and TCu380A, for illustration.