An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue. The effect of the oxytocin antagonist atosiban on preterm uterine activity in the human. Double-blind, randomized, controlled trial of atosiban and ritodrine in the treatment of preterm labor: a multicenter effectiveness and safety study.
This study was designed to evaluate the efficacy and safety of the oxytocin receptor antagonist atosiban in the treatment of preterm labor.
                A multicenter, double-blind, placebo-controlled trial with tocolytic rescue was designed. Five hundred thirty-one patients were randomized to receive, and 501 received, either intravenous atosiban (n = 246) or placebo (n = 255), followed by subcutaneous maintenance with the assigned agent. Standard tocolytics as rescue tocolysis were permitted after 1 hour of either placebo or atosiban if preterm labor continued. The primary end point was the time from the start of study drug to delivery or therapeutic failure. Secondary end points were the proportion of patients who remained undelivered and did not receive an alternate tocolytic at 24 hours, 48 hours, and 7 days.
                No significant difference was found in the time from start of treatment to delivery or therapeutic failure between atosiban and placebo (median, 25.6 days vs 21.0 days, respectively; P =.6). The percentages of patients remaining undelivered and not requiring an alternate tocolytic at 24 hours, 48 hours, and 7 days were significantly higher in the atosiban group than in the control group (all P < or =.008). A significant treatment-by-gestational age interaction existed for the 48-hour and 7-day end points. Atosiban was consistently superior to placebo at a gestational age of > or =28 weeks. Fourteen atosiban-treated patients and 5 placebo-treated patients were randomized at <24 weeks; the incidence of fetal-infant deaths was higher for the atosiban group at <24 weeks. Maternal-fetal adverse events were similar except for injection-site reactions, which occurred more often with atosiban.
                In this trial the treatment of patients in preterm labor with atosiban resulted in prolongation of pregnancy for up to 7 days for those at a gestational age > or =28 weeks, and this occurred with a low rate of maternal-fetal adverse effects. In addition, at a gestational age > or =28 weeks, the infant morbidity and mortality of atosiban-initiated standard care were similar to those with placebo-initiated standard care. Given that all patients in this study were eligible for tocolysis and that, in practice, nearly all patients who are eligible for a tocolytic receive one, the benefit of using atosiban is the placebo-like maternal-fetal side effect profile. These observations support the use of this oxytocin receptor antagonist in the treatment of patients in preterm labor with intact membranes. Efficacy and infant outcome data at <28 weeks are inconclusive. The purpose of this study was to test the hypothesis that infusion of the oxytocin antagonist atosiban results in decreased preterm uterine activity in the human.
                A randomized, double-blind, placebo-controlled trial was performed. One hundred twenty women from 20 to 36 weeks' gestation with a complaint of labor who had more than four uterine contractions per hour after intravenous hydration but no evidence of cervical changes were randomized to receive a 2-hour intravenous infusion of atosiban at a rate of 300 micrograms/min or placebo. Ond hundred-twelve subjects (56 in each arm) were suitable for analysis of efficacy. Both groups remained at bed rest and received hydration.
                The mean percent decrease in contraction frequency was greater in atosiban subjects compared with controls (55.3% +/- 36.3% vs 26.7% +/- 40.4%, mean +/- SD, p < 0.001). A minimal (< 20%) decrease or an increase in contraction frequency was noted in 25 placebo subjects (45%) and seven atosiban subjects (13%). There was no clinically or statistically significant change in maternal blood pressure or heart rate during the infusion. The only adverse experiences possibly related to the drug were nausea and vomiting in one atosiban patient.
                A 2-hour infusion of the oxytocin antagonist atosiban resulted in a significantly greater decline in contraction frequency compared with controls. Oxytocin appears to play a role in the maintenance of preterm uterine activity in the human. This study was undertaken to compare the efficacy and safety of intravenous administration of atosiban versus ritodrine for the treatment of preterm labor. Study Design: Women with preterm labor and intact membranes diagnosed at 23 to 33 gestational weeks (n = 247) were randomly assigned to treatment arms and received atosiban (6.75 mg intravenous bolus, 300 microg/min for 3 hours, then 100 microg/min intravenously) or ritodrine (0.10-0.35 mg/min intravenously) for as long as 18 hours. Tocolytic effectiveness was assessed in terms of the numbers of women who had not been delivered after 48 hours and after 7 days. Safety was assessed in terms of maternal side effects and neonatal morbidity. Secondary outcomes included mean gestational age at delivery and mean birth weight. An intent-to-treat analysis was performed with the Cochran-Mantel-Haenszel test.
                The proportion of women who had not been delivered at 48 hours was 84.9% (n = 107) in the atosiban group and 86.8% (n = 105) in the ritodrine group. At 7 days 92 women had still not been delivered in both the atosiban (73.0%) and ritodrine (76.0%) groups. Neither of these differences was statistically significant. The incidence of maternal cardiovascular side effects was substantially lower in the atosiban group (4.0% vs 84.3%, P <.001). In addition, intravenous therapy was terminated more frequently as a result of maternal adverse events in the ritodrine group (29.8%) than in the atosiban group (0.8%). The overall occurrences of fetal adverse events in the two treatment groups were comparable. Neonatal morbidity was similar between the treatment groups after adjustment for unbalanced enrollment of women with multiple pregnancies and for gestational ages within treatment groups.
                Atosiban was comparable in clinical effectiveness to conventional ritodrine therapy but was better tolerated than ritodrine, with no evidence of significant maternal or fetal adverse events. Neonatal morbidity, which was similar between the two treatment arms, was apparently related to the gestational age of the infant rather than to the exposure to either tocolytic agent.
This review failed to demonstrate the superiority of atosiban over betamimetics or placebo in terms of tocolytic efficacy or infant outcomes. The finding of an increase in infant deaths in one placebo controlled trial warrants caution. A recent Cochrane review suggests that calcium channel blockers (mainly nifedipine) are associated with better neonatal outcome and fewer maternal side-effects than betamimetics. However, a randomised comparison of nifedipine with placebo is not available. Further well-designed randomised controlled trials of tocolytic therapy are needed. Such trials should incorporate a placebo arm.
[Note: The 24 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]