atosiban and Fetal-Death

In addition to questions raised about the efficacy of many tocolytics, appropriate concern has been voiced about the safety of these potent drugs. Although some degree of risk for adverse effects with drugs promising a strong therapeutic effect can be accepted, caution needs to be exercised when benefits are marginal or unproven. Unfortunately, some of the tocolytics, most notably the betamimetics and magnesium sulfate, have been found to have considerable potential for adverse maternal cardiovascular and respiratory effects. Although less clearly established, the use of indomethacin appears to be associated with increased fetal and neonatal risks. Concerning magnesium sulfate, in addition to the well-known maternal effects, the accumulating evidence showing an increased frequency of adverse outcomes in the fetus and neonate has led to the recommendations to abandon its use entirely as a tocolytic. Given the limitations of our current state of knowledge, nifedipine would appear to be among the more efficacious and safer tocolytics available to use when properly indicated.

Topics: Adrenergic beta-Agonists; Calcium Channel Blockers; Cyclooxygenase Inhibitors; Female; Fetal Death; Fetal Diseases; Humans; Magnesium Sulfate; Obstetric Labor, Premature; Oxytocin; Pregnancy; Randomized Controlled Trials as Topic; Tocolytic Agents; Vasotocin

To compare the efficacy and safety of atosiban and salbutamol in the treatment of preterm labor.. A multicenter, double-blind, double-placebo, randomized, controlled trial. Women (n=241) diagnosed with preterm labor at 23-33 gestational weeks were enrolled and received either atosiban (n=119) or salbutamol (n=122). At randomization, women were stratified by gestational age (< or =28 weeks and >28 weeks). Atosiban (i.v. bolus dose of 6.75 mg, then 300 microg/min for 3h and 100 microg/min for up to 48h) and salbutamol (2.5-45 microg/min) were administered by i.v. infusion for up to 48h. Retreatment with study drug or an alternative tocolytic agent was allowed. Main outcome measures included tocolytic effectiveness which was assessed in terms of the number of women undelivered after 48h and 7 days. Tocolytic efficacy and tolerability were assessed in terms of the proportion of women undelivered and who did not require alternative tocolytic therapy at 48h and 7 days of starting treatment. Safety was assessed in terms of maternal side effects and neonatal morbidity.. Tocolytic effectiveness at 48h was 93.3 versus 95.0% (P=0.67) and after 7 days was 89.9 versus 90.1% (P=0.93) in the atosiban and salbutamol groups, respectively. Tocolytic efficacy and tolerability within 48h was 79.8 versus 75.2% (P=0.15), and after 7 days was 58.8 versus 46.3% (P=0.021) in the atosiban and salbutamol groups, respectively. Maternal adverse events, including serious events, occurred more frequently in the salbutamol group. Neonatal outcomes were comparable between the study groups.. The oxytocin antagonist atosiban was found to be better tolerated by both mother and fetus than salbutamol, with a comparable neonatal and infant safety profile, and atosiban was as effective as salbutamol in delaying threatened preterm birth. This study supports the clinical use of atosiban in the treatment of preterm labor.

Topics: Adrenergic beta-Agonists; Adult; Albuterol; Double-Blind Method; Female; Fetal Death; Hormone Antagonists; Humans; Infant Mortality; Infant, Newborn; Infant, Newborn, Diseases; Obstetric Labor, Premature; Pregnancy; Tocolytic Agents; Treatment Outcome; Uterine Contraction; Vasotocin

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.

Topics: Double-Blind Method; Female; Fetal Death; Fetal Distress; Gestational Age; Humans; Obstetric Labor, Premature; Placebos; Pregnancy; Time Factors; Tocolysis; Tocolytic Agents; Treatment Outcome; Vasotocin

It has been proposed that the rise in myometrial oxytocin receptor (OTR) concentrations at term triggers parturition. In the present study, we have shown that in vivo infusion of the beta2-adrenoceptor (beta2AR) antagonist ICI-118.551 in late pregnant rats prevents the rise in myometrial OTR binding normally seen during delivery. A reduced contractile responsiveness of uterine strips isolated from rats in labor when challenged with oxytocin (OT) and a slight shortening of gestation accompanied this effect. OTR mRNA levels were, however, unaltered after the treatment, suggesting that the effect of beta2AR blockade on myometrial OTR was posttranscriptional or due to influences on extra-myometrial tissue. Infusion of the OTR antagonist atosiban down-regulated OTR binding sites in the parturient myometrium and resulted in an impaired contractile response to OT without affecting gestational length. OTR gene expression did not change, as seen from unchanged OTR mRNA values. Neither atosiban nor ICI-118.551 infusions alone changed fetal mortality. A significant increase in the incidence of fetal deaths was found, however, when rats were treated with a combination of atosiban and ICI-118.551. This treatment also down-regulated myometrial OTR and weakened the contractile response to OT, but it did not change gestational length. We conclude that the timing and onset of a normal parturition as well as a favorable outcome seem to be independent of a rise in OTR. This fact cannot exclude the possibility that an increase in OTR is of importance in the genesis of preterm labor. We suggest that beta2 stimulation up-regulates OTR during delivery. This effect may partly be responsible for the tachyphylaxis seen after the use of beta2 agonists to control preterm labor. We further suggest that OTR stimulation up-regulates OTR during labor. The OTR down-regulation seen after atosiban treatment adds to the direct relaxing effect of atosiban on the myometrium. In view of this, atosiban may prove to be a more useful tocolytic than the traditionally used beta2 agonists.

Topics: Adrenergic beta-2 Receptor Antagonists; Adrenergic beta-Antagonists; Animals; Cell Membrane; Female; Fetal Death; Gestational Age; Hormone Antagonists; Myometrium; Oxytocin; Pregnancy; Pregnancy Outcome; Propanolamines; Rats; Receptors, Adrenergic, beta-2; Receptors, Oxytocin; RNA, Messenger; Uterine Contraction; Vasotocin