Inhibition Of Preterm Labor Research Articles

An update on the controversies of tocolytic therapy for the prevention of preterm birth

Acta Obstet Gynecol Scand 2003; 82: 1–9. © Acta Obstet Gynecol Scand 2003 Preterm birth is the major cause of perinatal mortality and morbidity in the developed world. Where there are no contraindications to their use, tocolytics can improve neonatal survival rates by approximately 3% per day between 23 and 27 weeks gestation with a concomitant reduction in morbidity. The ultimate aim of tocolytic therapy is to prolong pregnancy until growth and maturation is complete, but even short-term delay may enable the administration of antepartum glucocorticoids to reduce hyaline membrane disease or to arrange transfer to a center with neonatal intensive care facilities. Both of these have been shown to reduce neonatal mortality and morbidity. Until recently, none of the currently used tocolytics, whether licensed or unlicensed, were developed specifically for the inhibition of preterm labor and consequently, they exhibit various potentially serious side-effects. As a result of the recent licensing of the oxytocin antagonist, atosiban, developed for the treatment of preterm labor and due to its high utero-specificity, obstetricians have experienced an advance in their options for the management of spontaneous preterm labor.

An update on the controversies of tocolytic therapy for the prevention of preterm birth.

Preterm birth is the major cause of perinatal mortality and morbidity in the developed world. Where there are no contraindications to their use, tocolytics can improve neonatal survival rates by approximately 3% per day between 23 and 27 weeks gestation with a concomitant reduction in morbidity. The ultimate aim of tocolytic therapy is to prolong pregnancy until growth and maturation is complete, but even short-term delay may enable the administration of antepartum glucocorticoids to reduce hyaline membrane disease or to arrange transfer to a center with neonatal intensive care facilities. Both of these have been shown to reduce neonatal mortality and morbidity. Until recently, none of the currently used tocolytics, whether licensed or unlicensed, were developed specifically for the inhibition of preterm labor and consequently, they exhibit various potentially serious side-effects. As a result of the recent licensing of the oxytocin antagonist, atosiban, developed for the treatment of preterm labor and due to its high utero-specificity, obstetricians have experienced an advance in their options for the management of spontaneous preterm labor.

Pharmacologic Inhibition of Preterm Labor

Introduction Preterm birth is a significant public health and obstetric problem. While accounting for only 6–10% of all births, preterm delivery is responsible for 70–85% of neonatal morbidity and mortality. Approximately three fourths of these preterm births occur secondary to preterm labor or preterm rupture of membranes. Despite the advances in neonatal care and technology, these statistics have not changed dramatically over the last several decades. Obstetricians have approached this issue from preventative and therapeutic standpoints. Preventative measures and methods of identifying women at increased risk for preterm labor have met with limited success. These methods include risk scoring indices, home uterine activity monitoring, ultrasound evaluation of cervical length, serial digital cervical examinations, fetal fibronectin, and salivary estriol testing to name a few. Pharmacologic therapies have been used with the goal of decreasing the morbidity and mortality of prematurity by manipulating the process of parturit ion. This article will focus on the pharmacologic inhibition of labor with an initial overview of the contemporary understanding and approach to preterm labor, goals and criteria for labor inhibition, overview of the mechanisms of parturition and myometrial contractility, followed by a systematic and evidence-based approach to currently used tocolytic agents including betaadrenergic receptor agonists, magnesium sulfate, prostaglandin inhibitors, calcium channel blockers, oxytocin antagonists, and nitric oxide donors.

New developments in the management of preterm labor

Current management of preterm labor has not changed the incidence of preterm delivery; therefore, significant research effort has been concentrated on the search for new methods of management. New tocolytics like inhibitors of cyclooxygenase 2 and nitric oxide donors have been tested in animal models and in preliminary clinical trials with promising results. Inhibition of cervical ripening may be one alternative to tocolysis. This new approach has a potential to be a valuable method of management of preterm labor if human studies confirm the promising results reported in animals. Growing evidence suggests that premature delivery may be associated with infection or fetal growth abnormalities, with dire consequences to the fetus. If these associations are to be included in risk and benefit assessment, then inhibition of preterm labor may prove to be detrimental to the fetus.

The oxytocin antagonist atosiban versus the β‐agonist terbutaline in the treatment of preterm labor

Objective. To compare the efficacy and safety of atosiban and terbutaline for the inhibition of preterm labor.Methods. Two hundred and forty‐nine women diagnosed with preterm labor at 23–33 weeks of gestation were enrolled of whom 245 women received treatment, 116 with atosiban and 129 with terbutaline. At randomization, women were stratified by gestational age (≤28 weeks and >28 weeks). Atosiban (iv bolus dose of 6.75 mg, then 300 μg/min for 3 h and 100 μg/min thereafter) and terbutaline (5–20 μg/min) were administered by iv infusion for 13–18 h. Re‐treatment with study drug or an alternative tocolytic agent was allowed. Tocolytic effectiveness was assessed in terms of the number of women undelivered after 48 hours and 7 days and efficacy and tolerability in terms of the number of women remaining undelivered and not requiring alternative tocolytic therapy after 48 hours and 7 days of starting therapy. Safety was assessed in terms of maternal side effects and neonatal morbidity.Results. Tocolytic effectiveness at 48 hours was 86.1% vs 85.3%; p=0.783, and after 7 days it was 76.5% vs 67.4%; p=0.067, in the atosiban and terbutaline groups, respectively. Tocolytic efficacy and tolerability after 48 hours was 72.2% vs 68.2%; p=0.51 and after 7 days was 55.6% vs 43.4%; p=0.08 in the atosiban and terbutaline groups, respectively. Overall, there were fewer clinically important adverse events with atosiban than with terbutaline.Conclusions. The efficacy of atosiban in the inhibition of preterm labor was shown to be comparable to terbutaline. Atosiban had a superior safety profile compared with terbutaline in terms of maternal and fetal adverse events, and comparable infant outcomes.

The oxytocin antagonist atosiban versus the beta-agonist terbutaline in the treatment of preterm labor. A randomized, double-blind, controlled study

To compare the efficacy and safety of atosiban and terbutaline for the inhibition of preterm labor. Two hundred and forty-nine women diagnosed with preterm labor at 23-33 weeks of gestation were enrolled of whom 245 women received treatment, 116 with atosiban and 129 with terbutaline. At randomization, women were stratified by gestational age (< or =28 weeks and >28 weeks). Atosiban (iv bolus dose of 6.75 mg, then 300 microg/min for 3 h and 100 microg/min thereafter) and terbutaline (5-20 microg/min) were administered by iv infusion for 13-18 h. Re-treatment with study drug or an alternative tocolytic agent was allowed. Tocolytic effectiveness was assessed in terms of the number of women undelivered after 48 hours and 7 days and efficacy and tolerability in terms of the number of women remaining undelivered and not requiring alternative tocolytic therapy after 48 hours and 7 days of starting therapy. Safety was assessed in terms of maternal side effects and neonatal morbidity. Tocolytic effectiveness at 48 hours was 86.1% vs 85.3%; p=0.783, and after 7 days it was 76.5% vs 67.4%; p=0.067, in the atosiban and terbutaline groups, respectively. Tocolytic efficacy and tolerability after 48 hours was 72.2% vs 68.2%; p=0.51 and after 7 days was 55.6% vs 43.4%; p=0.08 in the atosiban and terbutaline groups, respectively. Overall, there were fewer clinically important adverse events with atosiban than with terbutaline. The efficacy of atosiban in the inhibition of preterm labor was shown to be comparable to terbutaline. Atosiban had a superior safety profile compared with terbutaline in terms of maternal and fetal adverse events, and comparable infant outcomes.

Editor's Choice

Editor's Choice

Inhibition of premature labor in sheep by a combined treatment of nimesulide, a prostaglandin synthase type 2 inhibitor, and atosiban, an oxytocin receptor antagonist

Objective: The aim of this study was to compare the effects of the selective prostaglandin synthase type 2 inhibitor nimesulide, alone or in combination with the oxytocin receptor antagonist atosiban, on the progression of glucocorticoid-induced premature labor in sheep. Effects on circulating maternal and fetal prostaglandin concentrations and on fetal well-being were also examined. Study Design: Premature labor was induced in ewes with long-term catheterized fetuses by infusion of dexamethasone (1 mg/d) starting at 138 ± 1 days’ gestation. Ewes also received an infusion of either nimesulide and atosiban (20.0 and 4.12 mg/kg per day, respectively; n = 5), nimesulide alone (20.0 mg/kg per day; n = 5), or vehicle only (n = 9). Plasma 13,14-dihydro-15-keto-prostaglandin F2α and prostaglandin E2 concentrations were measured before and during infusions in plasma samples obtained from the maternal and fetal carotid arteries and the utero-ovarian vein. Results: No fetuses from ewes treated with nimesulide and atosiban were delivered during treatment. These animals were killed electively 98.0 ± 6.8 hours after the commencement of dexamethasone induction. This was significantly longer than the delivery times for those ewes treated with nimesulide alone (71.2 ± 3.9 hours; n = 5) and for vehicle-treated ewes (51.4 ± 1.7 hours; n = 9). Both maternal and fetal plasma 13,14-dihydro-15-keto-prostaglandin F2α and prostaglandin E2 concentrations in nimesulide and atosiban–treated ewes and in nimesulide-treated ewes decreased during treatment. In contrast, vehicle-treated ewes showed a significant increase in maternal and fetal plasma 13,14-dihydro-15-keto-prostaglandin F2α and prostaglandin E2 concentrations during dexamethasone induction. Uterine electromyographic activity observed in nimesulide and atosiban–treated ewes was significantly suppressed with respect to activities in both vehicle- and nimesulide-treated ewes during the treatment period. All fetuses were alive at delivery or scheduled death. Conclusions: These results indicate that the combination of an inhibitor of prostaglandin endoperoxidase H synthase type 2 with an oxytocin receptor antagonist is more effective in inhibition of preterm labor than is treatment with a prostaglandin endoperoxidase H synthase type 2 inhibitor alone. The clinical use of atosiban to prevent the oxytocin-stimulated increase in uterine activity associated with labor in combination with nimesulide may permit reduction of the dose of nimesulide used to a level that has minimal impact on fetal well-being. (Am J Obstet Gynecol 2000;183:649-57.)

Efficacy of the selective prostaglandin synthase type 2 inhibitor nimesulide in blocking basal prostaglandin production and delaying glucocorticoid-induced premature labor in sheep

Objective: The purpose of the study was to determine the effects of selective prostaglandin synthase type 2 inhibitors on basal prostaglandin concentrations in the fetal and maternal circulations and on the labor-associated increase in prostaglandin production in sheep. Study Design: The effects of maternal nimesulide (0.01, 0.1, and 1 mg/kg) and 6-methoxy-2-naphthylacetic acid (1, 5, and 10 mg/kg) administration were examined (n = 5) at 134 ± 1 days’ gestation. At 138 days’ gestation premature labor was induced by fetal dexamethasone infusion (1 mg/d). Ewes were treated with either vehicle or nimesulide infusion (20 mg · d –1 · kg –1 , n = 5 per group). Results: Nimesulide and 6-methoxy-2-naphthylacetic acid decreased basal prostaglandin production in a concentration-dependent manner. Delivery of nimesulide-treated ewes was delayed by ≥17 hours with respect to that of control ewes (53.9 ± 2.6 hours). In 2 nimesulide-treated ewes labor did not progress to delivery despite membrane rupture. The increase in prostaglandin concentrations usually seen during dexamethasone-induced labor was abolished in nimesulide-treated ewes and also in their fetuses. Conclusions: Highly selective inhibitors of prostaglandin endoperoxidase H synthase 2 may be required to spare fetal prostaglandin production and limit potential side effects during the suppression of preterm labor. (Am J Obstet Gynecol 1999;180:1244-53.)

Comparison of Nifedipine and Ritodrine for the Treatment of Preterm Labor

Treatment of preterm labor with beta-sympathomimetics has been questioned because of the many maternal and fetal complications associated with its use. Nifedipine, a calcium antagonist, has been shown to suppress uterine activity in vitro and in vivo. A randomized prospective study was performed to compare the efficacy of nifedipine to ritodrine in the suppression of preterm labor. Data obtained from 42 women, of which 19 were randomized to the ritodrine group and 23 to the nifedipine group, were analyzed. Ritodrine and nifedipine proved to be equally effective in the suppression of preterm labor. However, the nifedipine group had fewer maternal and fetal complications.

Magnesium oxide is an effective alternative to terbutaline for suppression of preterm labour ???

Magnesium oxide is an effective alternative to terbutaline for suppression of preterm labour ???

Fetal resuscitation in a patient with varicella pneumonia and preterm labor

A primigravida presented at 33 weeks gestation with varicella pneumonia. Cardiotocography demonstrated repeated late decelerations of fetal heart rate. Cesarean section was indicated for contracted maternal pelvis and breech presentation, but was decided against because of the risks of anesthesia. Maternal and fetal improvement followed intrauterine resuscitation and suppression of preterm labor. Cesarean section was performed 9 days later after spontaneous rupture of membranes with excellent outcome. The same approach is suggested for similar cases

Myometrial desensitization after ritodrine infusion.

We have developed a model in pregnant sheep to investigate pharmacological agents used for suppression of preterm labor. This model allows repetitive determinations of uterine contractility and simultaneous measurements of myometrial receptor and postreceptor events. We used the model to study the beta-adrenergic agent ritodrine. We infused 11 pregnant sheep with ritodrine and 3 with physiological saline for 24 h. Oxytocin boluses were given before and at 5 and 22 h after onset of the infusion. Myometrial biopsies were obtained before and immediately after the infusion. After 22 h of ritodrine infusion, uterine contractility in response to the same oxytocin bolus was 50% greater than at 5 h (P less than 0.02). Myometrial membrane beta-adrenergic receptor density decreased 49% (P less than 0.005), and catecholamine-stimulated adenylate cyclase activity was reduced 70% (P less than 0.005). The model thus demonstrates that use of the beta-adrenergic agonist ritodrine in a clinically relevant manner results in tachyphylaxis of its effects on both physiological parameters and the receptor cascade system.

Life-Threatening Complications of Betamimetic Therapy for Preterm Labor Inhibition

Betamimetic administration for inhibition of preterm labor can result in a number of severe complications for the mother. An understanding of clinical situations that increase the risk of complications and suggested treatment of adverse effects are discussed in this review.

Cardiovascular collapse associated with oral terbutaline tocolytic therapy

{3-Mimetic agents are widely used for the inhibition of preterm labor because of their effects on the uterine myometrium. However, many additional effects can be seen in other organ systems which change both biophysical and biochemical parameters. Potentially, the most significant are the development of marked hypokalemia and pulmonary edema with or without the concomitant use of steroids. Subsequent to an adequate dosage of {3-mimetic agents, either terbutaline or ritodrine, maternal tachycardia usually occurs. Normally, the tachycardia that follows the use of these drugs is not considered to be pathologic or lifethreatening. We now report a case of supraventricular tachycardia with cardiovascular decompensation in a patient who was being treated for preterm labor with oral terbutaline.

Pharmacodynamics of ritodrine in pregnant women during preterm labor

We evaluated the relationship of ritodrine concentration to several maternal variables and to fetal heart rate in 17 women who received the drug for inhibition of preterm labor. Ritodrine was measured by high-performance liquid chromatography with electrochemical detection. Ritodrine increased maternal and fetal heart rate and decreased serum potassium in a dose-related manner, but wide variability was noted between patients and within individual patients. Tachyphylaxis of the maternal heart rate response to continuing treatment with ritodrine was seen in at least seven women. Maternal blood pressure, serum glucose concentration, and frequency of uterine contractions were changed by ritodrine treatment, but the changes in these variables were not closely correlated to the concentration of ritodrine (r ≤ 0.30 in all cases). The maximal infusion rate and the concentration of ritodrine in maternal serum after 4 hours of treatment were significantly (p < 0.001) correlated with the frequency of uterine contractions prior to treatment. Successful inhibition of labor was achieved with serum concentrations of 15 to 31 ng/ml in 10 of 17 women; in six of the other seven women, labor could not be inhibited in spite of serum concentrations of 90 to 146 ng/ml. Side effects, such as hypotension, vomiting, chest discomfort, and shortness of breath, were most commonly observed when the infusion rate and concentration of ritodrine were increasing.

381 EFFECTS OF MATERNAL RITODRINE THERAPY ON FETAL RAT BRAIN DEVELOPMENT

Ritrodrine is a beta-adrenergic agonist used for the inhibition of pre-term labor. As a potential activator of the cyclic AMP system, biochemical changes in the fetus might be anticipated after maternal treatment. Effects of maternal treatment with ritodrine on fetal rat brain development were investigated. A longterm treatment group (L) received ritodrine,3mg/kg/dose,IM q8h on days 18-22 of pregnancy.A short term treatment group (S) received one 3mg/kg I.V.dose on day 22. Controls for L and S received saline by the same procedures.Pups were delivered by C/section on day 22. Their body and brain weights and brain protein, DNA,cholesterol, glycogen,myelin basic protein and beta-adrenergic receptors (by binding of Dihydroalprenolol,DHA) were measured. No statistically significant changes were detected.Using this experimental model, there seem to be no adverse biochemical effects of Ritodrine on fetal rat brain development.

Pharmacologic inhibition of preterm labor

Preterm labor is responsible for a majority of cases of perinatal morbidity and deaths. Prevention of preterm labor is not usually possible; thus pharmacologic treatment is the only recourse available. Numerous agents have been used to treat preterm labor, but none has proved to be superior. This report reviews the current information available about the pharmacology of labor-inhibiting drugs and discusses the clinical approach to the management of preterm labor.