Efficacy of two intervals and two routes of administration of misoprostol for termination of early pregnancy: a randomised controlled equivalence trial

Background The most effective route and best interval between several doses of misoprostol to induce abortion have not been defined. Our aim was to assess the effects of the interval between multiple doses of misoprostol and the route of administration to terminate pregnancy. Methods 2066 healthy pregnant women requesting medical abortion with 63 days or less of gestation were randomly assigned within 11 gynaecological centres in six countries to the four treatment groups (three doses of 0.8 mg misoprostol given sublingually at 3-h intervals, vaginally 3 h, sublingually 12 h, and vaginally 12 h), stratifying by gestational age. This was an equivalence trial with a 5% margin of equivalence. The primary endpoints were efficacy of treatment to achieve complete abortion and to terminate pregnancy. The main efficacy analysis excluded women lost to follow-up. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN10531821. Findings Efficacy outcomes were analysed for 2046 women (99%), excluding 20 lost to follow-up. Complete abortion rates at 2-week follow-up were recorded for 431 (84%) in the sublingual and for 434 (85%) women in the vaginal group when misoprostol was given at 3-h intervals (difference 0.4%, 95% CI -4.0 to 4.9, p=0.85 equivalence shown), and for 399 (78%) in the sublingual and for 425 (83%) in the vaginal 12-h groups (4.6%, -0.2 to 9.5, p=0.06, equivalence not shown). In the 3-h groups, pregnancy continued in 29 (6%) women after sublingual. and in 20 (4%) women after vaginal administration. (difference 1.8%, 95% CI -0.8 to 4.4, p=0.19, equivalence shown); in the 12-h groups it continued in 47 (9%) after sublingual and in 25 (5%) after vaginal administration (4.4%, 1.2-7.5, p=0.01, vaginal better than sublingual). Differences for complete abortion between intervals for sublingual and vaginal routes were 6% (95% CI 1.0-10.6, p=0.02, 3 h better than 12 h) and 2% (-2.9 to 6.1, p=0.49, equivalence not shown), respectively; for continuing pregnancies they were 4% (0-4-6.8, p=0.03, 3 h better than 12 h) and 1% (-1.5 to 3.5, p=0.44, equivalence shown), respectively. Interpretation Administration interval can be chosen between 3 h and 12 h when misoprostol is given vaginally. If administration is sublingual, the intervals between misoprostol doses need to be short, but side-effects are then increased. With 12-h intervals, vaginal route should be used, whereas with 3-h intervals either route could be chosen.