Publication: Comparison of Two Doses and Two Routes of Administration of Misoprostol after Pre-Treatment with Mifepristone for Early Pregnancy Termination
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Published
2008
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1742-4755 (Electronic)
1742-4755 (Linking)
Date
2012-03-30
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BACKGROUND: It is not known whether a 400 microg dose of misoprostol has a similar efficacy as an 800 microg dose when administered sublingually or vaginally 24 hours after 200 mg mifepristone. METHODS: It is proposed to undertake a placebo-controlled, randomized, non-inferiority trial (3% margin of equivalence) of the two misoprostol doses when administered sublingually or vaginally using factorial design. A total of 3008 pregnant women (< 63 days of gestational age) who request legal termination of pregnancy will be recruited for the trial at 16 clinics in ten countries providing abortion services. Eligible women willing to join the study will be allocated randomly to one of the four treatment groups within each centre. Women in all treatment groups will first receive 200 mg mifepristone, followed 24 hours later by either 400 microg or 800 microg misoprostol, administered either sublingually or vaginally. The dose and route of administration of misoprostol will be blinded to women, each woman receiving four tablets vaginally and four tablets sublingually, two or four of which are 200 microg tablets of misoprostol and the rest are placebo tablets.The four treatment regimens will be compared in terms of: (i) their efficacy to induce complete abortion; (ii) induction-to-abortion interval when possible; (iii) the frequency of side effects; and (iv) women's perceptions. The initial judgment of the outcome of treatment is made at the follow-up visit on day 15 of the study and the final assessment four weeks later. It is estimated that the clinical phase will require 12-14 months for data collection.To compare the two routes and two doses, relative risks (RR) of failure to achieve a complete abortion and failure to terminate pregnancy and the two-sided 95% CIs will be calculated by standard methods, as well as risk differences and two-sided 95% CIs. The latter will be used to test the non-inferiority hypotheses (at 2.5% level of significance) for achieving complete abortion. The factorial structure will be taken into account in the analysis after testing the interaction. TRIAL REGISTRATION: ISRCTN87811512.
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Publication Two Mifepristone Doses and Two Intervals of Misoprostol Administration for Termination of Early Pregnancy : A Randomised Factorial Controlled Equivalence Trial(2009)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.Publication Comparison of Vaginal and Sublingual Misoprostol for Second Trimester Abortion : Randomized Controlled Equivalence Trial(2009)BACKGROUND: To identify an effective misoprostol-only regimen for the termination of second trimester pregnancy, we compared sublingual and vaginal administration of multiple doses of misoprostol in a randomized, placebo-controlled equivalence trial. METHODS: Six hundred and eighty-one healthy pregnant women requesting medical abortion at 13-20 weeks' gestation were randomly assigned within 11 gynaecological centres in seven countries into two treatment groups: 400 microg of misoprostol administered either sublingually or vaginally every 3 h up to five doses, followed by sublingual administration of 400 microg misoprostol every 3 h up to five doses if abortion had not occurred at 24 h after the start of treatment. We chose 10% as the margin of equivalence. The primary end-point was the efficacy of the treatments to terminate pregnancy in 24 h. Successful abortion within 48 h was also considered as an outcome along with the induction-to-abortion-interval, side effects and women's perceptions on these treatments. RESULTS: At 24 h, the success (complete or incomplete abortion) rate was 85.9% in the vaginal administration group and 79.8% in the sublingual group (difference: 6.1%, 95% CI: 0.5 to 11.8). Thus, equivalence could not be concluded overall; the difference, however, was driven by the nulliparous women, among whom vaginal administration was clearly superior to sublingual administration (87.3% versus 68.5%), whereas no significant difference was observed between vaginal and sublingual treatments among parous women (84.7% versus 88.5%). The rates of side effects were similar in both groups except for fever, which was more common in the vaginal group. About 70% of women in both groups preferred sublingual administration. CONCLUSIONS: Equivalence between vaginal and sublingual administration could not be demonstrated overall. Vaginal administration showed a higher effectiveness than sublingual administration in terminating second trimester pregnancies, but this result was mainly driven by nulliparous women. Fever was more prevalent with vaginal administration. Registered with International Standard Randomized Controlled Trial number ISRCTN72965671.Publication Alternative Versus Standard Packages of Antenatal Care for Low-Risk Pregnancy(2010)Background The number of visits for antenatal (prenatal) care developed without evidence of how many visits are necessary. The content of each visit also needs evaluation. Objectives To compare the effects of antenatal care programmes with reduced visits for low-risk women with standard care. Search strategy We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2010), reference lists of articles and contacted researchers in the field. Selection criteria Randomised trials comparing a reduced number of antenatal visits, with or without goal-oriented care, with standard care. Data collection and analysis Two authors assessed trial quality and extracted data independently. Main results We included seven trials (more than 60,000 women): four in high-income countries with individual randomisation; three in low-and middle-income countries with cluster randomisation (clinics as the unit of randomisation). The number of visits for standard care varied, with fewer visits in low-and middle-income country trials. In studies in high-income countries, women in the reduced visits groups, on average, attended between 8.2 and 12 times. In low-and middle-income country trials, many women in the reduced visits group attended on fewer than five occasions, although in these trials the content as well as the number of visits was changed, so as to be more 'goal oriented'. Perinatal mortality was increased for those randomised to reduced visits rather than standard care, and this difference was borderline for statistical significance (five trials; risk ratio (RR) 1.14; 95% confidence interval (CI) 1.00 to 1.31). In the subgroup analysis, for high-income countries the number of deaths was small (32/5108), and there was no clear difference between the groups (2 trials; RR 0.90; 95% CI 0.45 to 1.80); for low-and middle-income countries perinatal mortality was significantly higher in the reduced visits group (3 trials RR 1.15; 95% CI 1.01 to 1.32). Reduced visits were associated with a reduction in admission to neonatal intensive care that was borderline for significance (RR 0.89; 95% CI 0.79 to 1.02). There were no clear differences between the groups for the other reported clinical outcomes. Women in all settings were less satisfied with the reduced visits schedule and perceived the gap between visits as too long. Reduced visits may be associated with lower costs. Authors' conclusions In settings with limited resources where the number of visits is already low, reduced visits programmes of antenatal care are associated with an increase in perinatal mortality compared to standard care, although admission to neonatal intensive care may be reduced. Women prefer the standard visits schedule. Where the standard number of visits is low, visits should not be reduced without close monitoring of fetal and neonatal outcome.Publication The Use of Placebo in a Trial of Rectal Artesunate as Initial Treatment for Severe Malaria Patients En Route to Referral Clinics : Ethical Issues(2010)Placebo-controlled trials are controversial when individuals might be denied existing beneficial medical interventions. In the case of malaria, most patients die in rural villages without healthcare facilities. An artesunate suppository that can be given by minimally skilled persons might be of value when patients suddenly become too ill for oral treatment but are several hours from a facility that can give injectable treatment for severe disease. In such situations, by default, no treatment is (or can be) given until the patient reaches a facility, making the placebo control design clinically relevant; alternative bioequivalence designs at the facility would misrepresent reality and risk incorrect conclusions. We describe the ethical issues underpinning a placebo-controlled trial in severe malaria. To protect patients and minimise risk, all patients were referred immediately to hospital so that each had a higher chance of prompt treatment through participation. There was no difference between artesunate and placebo in patients who reached clinic rapidly; among those who could not, a single artesunate suppository significantly reduced death or permanent disability, a finding of direct and indirect benefit to patients in participating villages and elsewhere.Publication Fiscal Risks from Early Termination of Public-Private Partnerships in Infrastructure(Washington, DC: World Bank, 2022-03-15)Public-private partnerships (PPPs) in infrastructure provision have expanded around the world since the early 1990s. Well-structured PPPs can unleash efficiency gains, but PPPs create liabilities for governments, including contingent ones. This paper assesses the fiscal risks from contingent liabilities from early termination of PPPs in a sample of developing countries. It analyzes the drivers of early termination and identifies systematic contractual, institutional, and macroeconomic factors that can help predict the probability that a PPP project will be terminated early, using a flexible parametric hazard regression. Using the probability distributions from the regression analysis, it simulates scenarios of fiscal risks for governments from early termination of PPPs in the electricity and transport sectors, adopting a value-at-risk approach. The findings indicate that the rate of early terminations decreases with direct government support, greater constraints on executive power, and the award of the PPP by subnational governments; it increases with project size and macro-financial shocks. The simulations show that fiscal risks from infrastructure PPP portfolios are not negligible in some countries, reaching as high as 2.8 percent of GDP. A severe macro-financial shock substantially increases the estimates, with the value at risk the year after the shock 11–20 times larger.
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