SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. The role Of Oxytocin and Vasopression in the Initiation of Labour
  5. The Development of Oxytocin Antagonists
  6. Chemical Structure, Mechanism of Action and Basic Pharmacology of Oxytocin and Oxytocin Antagonists
  7. Theoretical Risks of Adverse Effects from Oxytocic Antagonists
  8. Clinical Studies of Atosiban in Pregnant Women
  9. References

The perfect tocolytic agent, which is completely safe for both the mother and fetus and, which will inhibit uterine contractions and stop preterm labour in every case does not exist and the search continues. Recently, research into a new group of tocolytic agents (the oxytocic antagonists) has led to the introduction of a new licensed drug, atosiban. Since the early 1950s, modifications of the oxytocin molecule have resulted in many analogues and antagonists, though initially none emerged as potentially useful drugs. Further modifications resulted in full uterotonic antagonism in animal models before an analogue was found that inhibited vasopressin-stimulated uterine contractions in non-pregnant healthy women. In vitro and animal models suggested the molecule was fully antagonistic, although it was found to be only partially agonistic in women. Further developments led to two modified oxytocin molecules with higher receptor affinity for human myometrium, both of which lacked agonism in humans. The analogue, atosiban, was found to be more potent and so was chosen for clinical evaluation in dysmenorrhoea and preterm labour. The first clinical reports were open label, observational pilot studies. Randomised, double-blind, phase II placebo-controlled studies followed showing that atosiban was significantly more effective than placebo with very few side effects. Dose-response studies and phase III studies in which study or placebo groups could use alternative tocolytic agents also suggested that atosiban was an effective tocolytic agent with very few adverse events. The recent worldwide comparative study of atosiban versus different beta-agonists represents the largest and most strictly controlled study of tocolytics ever published. Atosiban was found to be at least as effective as the beta-agonists as a tocolytic agent, but significantly less likely to result in maternal cardiovascular side effects or the need to discontinue therapy as a result of unacceptable side effects.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. The role Of Oxytocin and Vasopression in the Initiation of Labour
  5. The Development of Oxytocin Antagonists
  6. Chemical Structure, Mechanism of Action and Basic Pharmacology of Oxytocin and Oxytocin Antagonists
  7. Theoretical Risks of Adverse Effects from Oxytocic Antagonists
  8. Clinical Studies of Atosiban in Pregnant Women
  9. References

The perfect tocolytic that is completely safe for the mother and the fetus and that will inhibit uterine contractions in every case and stop preterm labour does not exist and is unlikely to be discovered. Until recently, the only tocolytic agents licensed for use in Europe were the β2-agonists, such as ritodrine, salbutamol, terbutaline, hexaprenaline and fenoterol. Unfortunately, due to lack of specificity, β2-agonists also cause cardiovascular, metabolic and constitutional side effects.

By nature of their physiological adaptations to pregnancy, pregnant women are at increased risk of pulmonary oedema1 and if exposed to β2-agonists, used either inappropriately or without appropriate monitoring, have a much higher risk of serious adverse effects, such as pulmomary oedema and, rarely, maternal death. Consequently, the Royal College of Obstetricians and Gynaecologists have issued recommendations for the monitoring of women receiving β2-agonists for the treatment of spontaneous preterm labour2, which includes:

  • 1
    maternal pulse at least every 15 minutes
  • 2
    maternal blood pressure initially every 15 minutes
  • 3
    maternal blood glucose every 4 hours
  • 4
    strict record of maternal input and output to monitor fluid balance
  • 5
    maternal serum urea and electrolytes at least every 24 hours
  • 6
    auscultation of the maternal lung bases every 4 hours.

As a result of these, and occasionally serious adverse effects, many obstetricians find the use of β2-agonists unacceptable, and in many countries β2-agonists have been taken off the market by regulatory bodies or manufacturers and distributing companies themselves. This has led to the use of unlicensed tocolytic agents, such as prostaglandin synthetase inhibitors, magnesium sulphate, nitric oxide donors, or calcium antagonists. Like the β2-agonists, none of these agents have been developed specifically to treat preterm labour, and as a result they all have fetomaternal adverse effects. In addition, none have been subjected to well-controlled studies of sufficient sample size to provide the evidence required to satisfy regulatory bodies. The evidence pertaining to the efficacy and safety of these unlicensed drugs as well as the β2-agonists has recently been comprehensively reviewed3.

The aetiology of spontaneous term labour as well as spontaneous preterm labour is not fully understood. As investigators have developed a greater understanding of the role of oxytocin in term and spontaneous preterm labour, the potential for a more specific effect in the target organ—the myometrium—with a reduced rate of side effects using an oxytocin receptor antagonist has been explored. This review outlines the rationale behind the development, introduction into clinical practice and clinical experience of oxytocin antagonists for the treatment of spontaneous preterm labour.

The role Of Oxytocin and Vasopression in the Initiation of Labour

  1. Top of page
  2. Abstract
  3. Introduction
  4. The role Of Oxytocin and Vasopression in the Initiation of Labour
  5. The Development of Oxytocin Antagonists
  6. Chemical Structure, Mechanism of Action and Basic Pharmacology of Oxytocin and Oxytocin Antagonists
  7. Theoretical Risks of Adverse Effects from Oxytocic Antagonists
  8. Clinical Studies of Atosiban in Pregnant Women
  9. References

As an important stimulator of myometrial contractility, both term and preterm, the role of oxytocin and its receptor in human parturition has been postulated and studied over the last 20 years4. The aetiology and initiation of preterm labour is multifactorial. Approaching 37 weeks gestation, spontaneous preterm labour is likely to be similar to physiological term labour. In contrast, though the final common pathway may be the same, spontaneous preterm labour at much earlier gestations is likely to be pathological as a result of an abnormal signal. Preterm labour may be regarded as a syndrome in which oxytocin plays an important part in the common mechanism of labour.

It is not known whether the onset of labour is associated with an increase in plasma concentration of oxytocin. However, it is known that oxytocin and vasopressin are released in a pulsatile manner from the neurohypophysis and the frequency of this pulsatile release into plasma increases immediately prior to labour. A circadian rhythm of oxytocin release has been identified and the nocturnal peak and plasma concentration of oxytocin parallels the increase in uterine activity5. The myometrium, both term and preterm, contains receptors for both oxytocin and vasopressin. Vasopressin receptors in the myometrium and uterine vasculature are of type V1a distinctly different from the vasopressin V2 receptors, regulating kidney function and the vasopressin V1b receptors of the anterior pituitary. Receptor binding studies suggest that oxytocin acts both on its own receptor and to some extent on the V1a and that vasopressin also activates the oxytocin receptor. The smooth muscle activity of uterine arterial walls is also increased by vasopressin V1a receptors6. The contractile effect of oxytocin on the myometrium is also partly due to an increase in oxytocin receptor concentrations and women in spontaneous preterm labour have higher oxytocin receptor concentrations than women at term who are not in labour (Fig. 1).

image

Figure 1. Oxytocin receptors in human myometrium during pregnancy and during preterm and term labour.

Download figure to PowerPoint

There is also a potential for a paracrine role of oxytocin since oxytocin gene expression has been demonstrated in the placenta, fetal membranes and decidua7. Oxytocin has also been shown to enhance prostaglandin release from the decidua and fetal membranes, which potentiates many of the other actions of oxytocin5. Oxytocin mRNA levels have also been shown to increase in human choriodecidua during labour. Whether or not oxytocin is released from these sites in amounts sufficient to have an effect on the uterus is uncertain.

Fuchs and Fuchs8 have proposed that the primary stimulant of myometrial contractility during labour should be (1) myometrial specific, (2) available in sufficient quantities to initiate labour (ie should be stored and available for immediate use), (3) secreted in response to maternal and fetal stimuli and (4) closely regulated in order to avoid untimely initiation of labour (that is to say through the availability of its receptors). Fuchs has argued that oxytocin is the only compound to meet these requirements. In contrast, prostaglandins are not specific for the uterus, do not have a release mechanism, which permits precise control, do not have an end organ sensitivity, which is low in pregnancy and high in labour, and do not have a systemic release, which will result in synchronous contractions.

The Development of Oxytocin Antagonists

  1. Top of page
  2. Abstract
  3. Introduction
  4. The role Of Oxytocin and Vasopression in the Initiation of Labour
  5. The Development of Oxytocin Antagonists
  6. Chemical Structure, Mechanism of Action and Basic Pharmacology of Oxytocin and Oxytocin Antagonists
  7. Theoretical Risks of Adverse Effects from Oxytocic Antagonists
  8. Clinical Studies of Atosiban in Pregnant Women
  9. References

Since Du Vigneaud et al.9 proposed the structure of oxytocin some 50 years ago, many analogues and antagonists have been studied as modifications of the oxytocin molecule. The nonapeptide, oxytocin, was the first peptide hormone to be used in a clinical setting. While many of the oxytocin antagonists produced were helpful in understanding the role of the parent hormone, until recently, none have emerged as potentially useful therapeutic agents. In 1960, changes to the parent molecule at position 2 resulted in an analogue, which had partial uterotonic antagonism10, but it was not until 1981, that full oxytocin antagonism in an analogue altered at position 2 could be shown in the rat uterus (in vivo) and in pregnant and non-pregnant human myometrium (in vitro)11.

It was around this time that the Food and Drug Administration in the USA approved the licensing of ritodrine hydrochloride to treat preterm labour. It is interesting to note that in the studies of ritodrine used for licensing, ritodrine was compared with a control group in whom alcohol was used as a tocolytic. Alcohol is a form of oxytocin antagonist, since it inhibits the release of oxytocin and vasopressin from the neurohypophysis; it also blocks the effect of these hormones on the myometrium.

In 1983, a further analogue, different at position 2 to the parent molecule, was found to inhibit vasopressin-stimulated uterine contractions in healthy, non-pregnant women but had partial agonism12. Between 1983 and 1986 changes to positions 1, 2, 4 and 8 of the parent molecule resulted in an analogue, which had higher receptor affinity in human myometrium (in vitro) and rat uterus (in vivo and in vitro)13,14. In 1985, two of these analogues, which differed from each other at position 4, were found to inhibit vasopressin-stimulated uterine contractions in non-pregnant women15. Both lacked agonism, so were considered full oxytocic antagonists. One of these (atosiban) was more potent than the other and so was chosen for further clinical evaluation for both dysmenorrhoea and preterm labour. The collaboration and the pioneering work of Dr Per Melin and Professor Mats Åkerlund has been covered more comprehensively elsewhere16,17.

During this time, Duphar BV, Weesp, Holland, the manufacturers and distributors of ritodrine hydrochloride, recorded an unacceptably high incidence of pulmonary oedema with the use of beta-agonists in the USA as part of its post-marketing surveillance strategy. As a result, they advised against the use of intravenous (IV) fluids for preloading prior to beta-agonist therapy1.

The theory behind preloading with IV fluids may not have been recognised at the time but was probably used, however inadvertently, because of the effect that hydration has on the stimulation of oxytocin and V1a receptors in the myometrium. Theoretically, an increase in IV fluids increases the need for a diuresis, which results in a decrease in the secretion of vasopressin with a subsequent decrease in the stimulation of both oxytocin and V1a receptors in the myometrium, with a resultant decrease in uterine activity. As a result of this, it is important that all studies on tocolytic therapy correct for the use of IV hydration for fluid preloading.

Chemical Structure, Mechanism of Action and Basic Pharmacology of Oxytocin and Oxytocin Antagonists

  1. Top of page
  2. Abstract
  3. Introduction
  4. The role Of Oxytocin and Vasopression in the Initiation of Labour
  5. The Development of Oxytocin Antagonists
  6. Chemical Structure, Mechanism of Action and Basic Pharmacology of Oxytocin and Oxytocin Antagonists
  7. Theoretical Risks of Adverse Effects from Oxytocic Antagonists
  8. Clinical Studies of Atosiban in Pregnant Women
  9. References

Oxytocin is a nonapeptide consisting of a ring of six amino acids and a tail of three amino acids, which differs from vasopressin at positions 3 and 8 of the amino acid sequence. Atosiban is an analogue of oxytocin that is modified at positions 1, 2, 4 and 8 of the parent molelcule. Atosiban [1-deamino-2-D-Tyr (OEt)-4-Thr-8-Orn] (Fig. 2). Oxytocin is a synthetic compound, which is a competitive oxytocin receptor antagonist that binds to membrane bound myometrial cell oxytocin receptors resulting in (1) dose-dependent inhibition of oxytocin stimulated inositol triphosphate (IP3) production with a decreased release of stored intracellular calcium from the sarcoplasmic reticulum, (2) closure of voltage gated channels in myometrial cell membranes to prevent influx of calcium into the myometrial cell, (3) the prevention of oxytocin mediated release of prostaglandins from decidua and fetal membranes, which potentiate (1) and (2).

image

Figure 2. Structures of oxytocin and the oxytocin antagonist atosiban, which is modified at positions 1, 2, 4 and 8 of the oxytocin molecule.

Download figure to PowerPoint

Theoretical Risks of Adverse Effects from Oxytocic Antagonists

  1. Top of page
  2. Abstract
  3. Introduction
  4. The role Of Oxytocin and Vasopression in the Initiation of Labour
  5. The Development of Oxytocin Antagonists
  6. Chemical Structure, Mechanism of Action and Basic Pharmacology of Oxytocin and Oxytocin Antagonists
  7. Theoretical Risks of Adverse Effects from Oxytocic Antagonists
  8. Clinical Studies of Atosiban in Pregnant Women
  9. References

Although atosiban has affinity for V1a, and V1b and V2 as well as oxytocin receptors, there are no clinical data to suggest any adverse effects on the cardiovascular, renal or central nervous systems. Oxytocin has a significant physiological effect on the mammary gland with respect to the removal of milk and theoretically atosiban could interfere with its function. While oxytocin antagonists have been shown to inhibit milk let down when administered to lactating animals, there seems to be little risk of this in women who receive atosiban antepartum. This is because the effect of the drug is reversible and of comparatively short duration due to a half-life of only 12 minutes. In the same way, there is no evidence of an adverse effect causing uterine atony and postpartum haemorrhage. Atosiban crosses the placenta, but umbilical venous blood levels are only 10% of maternal uterine vein levels. There is also a theoretical risk that women exposed to oxytocin antagonists over a long period of time may develop increased sensitivity to oxytocin, as a result of up-regulation of oxytocin receptors with an increased sensitivity to endogenous oxytocin.

To test this effect, Phaneuf et al.18 examined the effect of oxytocin on intracellular IP3, calcium mobilisation and oxytocin receptor numbers in cultured myometrial cells from pregnant women. Long term incubation with oxytocin resulted in desensitisation of the cells to oxytocin accompanied by a loss of oxytocin receptors. In contrast, long term exposure to atosiban did not affect oxytocin-induced IP3 formation, calcium mobilisation or oxytocin receptor numbers. This indicates that in contrast to oxytocin exposure, long term exposure to atosiban does not alter the sensitivity of the pregnant myometrium to oxytocin. Long term follow up in clinical studies have not shown any adverse effects in infants born to women who received atosiban antenatally.

Clinical Studies of Atosiban in Pregnant Women

  1. Top of page
  2. Abstract
  3. Introduction
  4. The role Of Oxytocin and Vasopression in the Initiation of Labour
  5. The Development of Oxytocin Antagonists
  6. Chemical Structure, Mechanism of Action and Basic Pharmacology of Oxytocin and Oxytocin Antagonists
  7. Theoretical Risks of Adverse Effects from Oxytocic Antagonists
  8. Clinical Studies of Atosiban in Pregnant Women
  9. References

Due to constraints in the length of this review, a fuller account of the aims, settings, types of studies, patients, methods and results of clinical trials involving atosiban in pregnant women can be found elsewhere17. In 198719 and 198920, the first open-label observational pilot studies of atosiban in pregnant women were reported. It was around this time, that the Canadian Preterm Labour Investigators' Group reported a placebo-controlled trial of ritodrine for the treatment of preterm labour21. In that study, they confirmed the meta-analysis by King et al.22 in which β2-agonists were shown to delay delivery for a short time, but were not associated with a reduction in perinatal mortality or morbidity. Following the publication of the Canadian Preterm Labour Investigators' Group, there was a call for reappraisal of the use of β2-agonists in the USA. As a result, there was a marked reduction in their use in the USA.

In 1994, the first randomised, double-blind, placebo-controlled trial evaluating the use of IV atosiban on uterine contractility was published. Women with documented evidence of cervical change were excluded from the study, therefore only including women in threatened spontaneous preterm labour rather than established preterm labour. However, it was still helpful to evaluate the effect of the drug in arresting uterine contractility preterm23.

In 1996, a randomised, double-blind, comparative controlled study, evaluated the effectiveness of four dosage regimens of atosiban compared with the standard administration of ritodrine. All but the lowest dose of atosiban was comparable with ritodrine at treating spontaneous preterm labour24.

The findings from these phase II studies, conducted between 1994 and 1996, was that atosiban was effective at stopping uterine contractions with relatively few side effects. This gave the confidence to proceed with a phase III, randomised, double-blind, placebo-controlled trial. Due to the reluctance to give placebo to women in early preterm labour, this study (by Romero et al.25) had in the methodology the option of tocolytic rescue therapy for women who after an hour or more failed to show any response. The results showed that women in preterm labour after 28 weeks gestation given atosiban were significantly less likely to deliver within 7 days or require alternative tocolytic therapy during that time25.

In the same year, Valenzuela et al. published the only study to date on the use of IV atosiban for maintenance therapy following inhibition of uterine contractions. This multicentre, randomised, double-blind, placebo-controlled trial showed that a continuous subcutaneous infusion with a syringe pump of atosiban resulted in significantly longer delay before recommencement of uterine contractions compared with placebo. Except for local inflammation at the injection site with atosiban, the adverse event profile for both atosiban and placebo were comparable26.

In 2001, the worldwide atosiban versusβ2-agonist study group reported their results27. This is the largest tocolytic study conducted to date and took place in nearly 80 centres in eight countries in North America, Northern Europe and Oceania. The study design was a randomised, double-blind, double-dummy, controlled comparative trial to compare the safety and efficacy of atosiban with three different β2-agonists (ritodrine, terbutaline and salbutamol). Twenty-seven centres in Northern Europe compared atosiban with terbutaline and 37 centres in France and Australia compared atosiban with salbutamol. Fifteen centres in Canada and Israel compared atosiban with ritodrine.

Inclusion and exclusion criteria were particularly strict. Specifically, no women were recruited after 34 weeks gestation, and as well as uterine contractions, there had to be evidence of cervical dilatation and shortening of the cervix. Any women who had received beta-agonists within 6 hours of admission or prostaglandin synthetase inhibitors within 12 hours of admission were excluded from the study. The methodology permitted alternative tocolytic therapy if the study drug caused unacceptable side effects or if there was strict evidence of progression of labour despite giving study drug. In addition, the methodology permitted retreatment so that, provided women had initially responded to the study drug by inhibition of their contractions, if they started contracting again and fulfilled strict protocol requirements, they could be retreated with the same study drug.

On an intention-to-treat analysis (included all women whether or not they received study drug or received study drug as per protocol and whether or not they received alternative tocolytic agents or required retreatment), there was no difference in the effectiveness between β2-agonists and atosiban. When only women who received study drug as per protocol were examined, atosiban was found to be more efficacious than β2-agonists, with a statistically significant reduction in the need to use alternative tocolytic therapy and in the number of women who delivered within 7 days of the start of treatment. With respect to safety, atosiban resulted in a 10-fold decrease (from 80% to 8%) of cardiovascular side effects and a statistically significant 15-fold decrease (from 15% to 1%) in the need to discontinue therapy because of unacceptable side effects (P < 0.0001). There were three cases of pulmonary oedema all of which occurred in women following β2-agonist therapy.

The study concluded that atosiban was at least as effective as ritodrine when measured on an intention-to-treat analysis. In addition, atosiban was more efficacious than beta-agonists in women who received study drug as per protocol, and by any analysis, showed a much safer safety profile. The authors of the report concluded that atosiban represented an advance in tocolytic therapy over existing agents27.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. The role Of Oxytocin and Vasopression in the Initiation of Labour
  5. The Development of Oxytocin Antagonists
  6. Chemical Structure, Mechanism of Action and Basic Pharmacology of Oxytocin and Oxytocin Antagonists
  7. Theoretical Risks of Adverse Effects from Oxytocic Antagonists
  8. Clinical Studies of Atosiban in Pregnant Women
  9. References
  • 1
    Lamont RF. The pathophysiology of pulmonary oedema with the use of beta-agonists. Br J Obstet Gynaecol 2000;107: 439444.
  • 2
    Royal College of Obstetricians and GynaecologistsBeta-agonists for the care of women in labour. Guideline No. 1. London : RCOG Press, 1997.
  • 3
    Besinger RE, Iannucci TA. Tocolytic therapy. In: ElderMG, RomeroR, LamontRF editors. Preterm Labour. 1997: 243297Churchill Livingstone, New York :
  • 4
    Fuchs A-R, Fuchs F, Husslein P, Soloff MS, Fernstrom MJ. Oxytocin receptors and human parturition: a dual role for oxytocin in the initiative of labor. Science 1982;215: 13961398.
  • 5
    Fuchs A-R, Behrens O, Liu HC. Correlation of nocturnal increase in plasma oxytocin with a decrease in plasma estradiol/progesterone ratio in late pregnancy. Am J Obstet Gynecol 1992;167: 159163.
  • 6
    Melin P. Development of an oxytocin antagonist—Atosiban. Res Clin Forums 1994;16: 155170.
  • 7
    Chibbar R, Miler FC, Mitchell BF. Synthesis of oxytocin in amnion, chorion and decidua may influence the timing of human parturition. J Clin Invest 1993;91: 185192.
  • 8
    Fuchs AR, Fuchs F. Endocrinology of human parturition: a review. Br J Obstet Gynaecol 1984;91: 948967.
  • 9
    Du Vigneaud V, Ressler C, Trippett S. The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin. J Biol Chem 1953;205: 949957.
  • 10
    Law HD, du Vigneaud V. Synthesis of 2p-methoxyphenylalanine oxytocin (O-Methyl-oxytocin) and some observations on its pharmacological behaviour. J Am Chem Soc 1960;82: 45794581.
  • 11
    Melin P, Vilhardt H, Lindeberg G, Larsson L-E, Akerlund M. Inhibitory effect of O-alkylated analogues of oxytocin and vasopressin on human and rat myometrial activity. J Endocrinol 1981;88: 173180.
  • 12
    Akerlund M, Stromberg P, Forsling ML, Melin P, Vilhardt H. Inhibition of vasopressin effects on the uterus by a synthetic analogue. Obstet Gynecol 1983;62: 309312.
  • 13
    Melin P, Trojnar J, Vilhardt H, Akerlund M. Uterotonic oxytocin and vasopressin antagonists with minimal structure modifications. In: HrubyVJ, RichDH. Peptides: Structure and Function Proceedings of the 8th American Peptide Symposium. Rockford , USA : Pierce Chemical, 1983: 361365.
  • 14
    Melin P, Trojnar J, Johansson B, Vilhardt H, Åkerlund M. Synthetic anatagonists of the myometrial response to vasopressin and oxytocin. J Endocrinol 1986;111: 125131.
  • 15
    Akerlund M, Carlsson AM, Melin P, Trojnar J. The effect on the human uterus of two newly developed competitive inhibitors of oxytocin and vasopressin. Acta Obstet Gynecol Scand 1985;64: 499504.
  • 16
    Åkerlund M. Oxytocin antagonists in the treatment of preterm labour. Fet Mat Med Rev 2002;13: 3141.
  • 17
    Lamont RF, Greenfield P. Anti-oxytocic tocolytic agents. Yearbook of the Royal College of Obstetricians and Gynaecologists, 10. London : RCOG Press, 2002: 30140.
  • 18
    Phaneuf S, Asboth G, Mackenzie IZ, Melin P, Lopez-Bernal A. Effect of oxytocin antagonists on the activation of human myometrium in vitro: Atosiban prevents oxytocin-induced desensitisation. Am J Obstet Gynecol 1994;171: 16261634.
  • 19
    Akerlund M, Stromberg P, Hauksson A, et al. Inhibition of uterine contractions of premature labour with an oxytocin analogue. Results from a pilot study. Br J Obstet Gynaecol 1987;94: 10401044.
  • 20
    Andersen L-F, Lyndrup J, Akerlund M, Melin P. Oxytocin receptor blockade: a new principle in the treatment of preterm labour. Am J Perinatol 1989;6: 196199.
  • 21
    The Canadian Preterm Labor Investigators GroupTreatment of preterm labor with the beta-adrenergic agonist ritodrine. N Engl J Med 1992;327: 308312.
  • 22
    King J, Grant A, Keirse MJ, Chalmers I. Beta-mimetics in preterm labor: an overview of the randomized controlled trials. Br J Obstet Gynaecol 1988;95: 211222.
  • 23
    Goodwin TM, Paul RP, Silver H, et al. The effect of the oxytocin antagonist atosiban on preterm uterine activity in the human. Am J Obstet Gynecol 1994;170: 474478.
  • 24
    Goodwin TM, Valenzuela GJ, Silver H, Creasy G, Atosiban Study GroupDose ranging study of the antagonist atosiban in the treatment of preterm labor. Obstet Gynecol 1996;88: 331336.
  • 25
    Romero R, Sibai BM, Sanchez-Ramos L, et al. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 2000;182: 11731183.
  • 26
    Valenzuela GJ, Sanchez-Ramos L, Romero R, et al. Maintenance treatment of preterm labor with the oxytocin antagonist atosiban. Am J Obstet Gynecol 2000;182: 11841190.
  • 27
    The Worldwide Atosiban versus Beta-agonists Study GroupEffectiveness and safety of the oxytocin antagonist Atosiban versus beta-adrenergic agents in the treatment of preterm labour. Br J Obstet Gynaecol 2001;108: 133142.