Oxytocin Antagonists for the Management of Preterm Birth: A Review

ABSTRACT

Preterm birth, the leading cause of neonatal morbidity and mortality, is estimated at incidence of 12.7% of all births, which has not decreased over the last four decades despite intensive antenatal care programs aimed at high-risk groups, the widespread use of tocolytics, and a series of other preventive and therapeutic interventions. Oxytocin antagonists, namely atosiban, represent an appealing choice that seems to be effective with apparently fewer side effects than the traditional tocolytics. This article reviews the available literature on the pharmacokinetics, mode of administration, and clinical utility of oxytocin antagonists for acute and maintenance tocolysis with special emphasis on its safety profile.

KEYWORDS

Oxytocin antagonists - tocolysis - preterm labor - adverse effects - dose

REFERENCES

• 1 Hamilton B E, Martin J A, Ventura S J. Births: preliminary data for 2007.  Natl Vital Stat Rep. 2009;  57 1-23
• 2 Copper R L, Goldenberg R L, Creasy R K et al.. A multicenter study of preterm birth weight and gestational age-specific neonatal mortality.  Am J Obstet Gynecol. 1993;  168 (1 Pt 1) 78-84
• 3 Morrison J C. Preterm birth: a puzzle worth solving.  Obstet Gynecol. 1990;  76 (1 Suppl) 5S-12S
• 4 Akerlund M, Carlsson A M, 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;  64 499-504
• 5 Engstrøm T, Bratholm P, Vilhardt H, Christensen N J. Effect of oxytocin receptor and beta2-adrenoceptor blockade on myometrial oxytocin receptors in parturient rats.  Biol Reprod. 1999;  60 322-329
• 6 Goodwin T M, Millar L, North L, Abrams L S, Weglein R C, Holland M L. The pharmacokinetics of the oxytocin antagonist atosiban in pregnant women with preterm uterine contractions.  Am J Obstet Gynecol. 1995;  173 (3 Pt 1) 913-917
• 7 Lundin S, Broeders A, Melin P. Pharmacokinetic properties of the tocolytic agent [Mpa1, D-Tyr(Et)2, Thr4, Orn8]-oxytocin (antocin) in healthy volunteers.  Clin Endocrinol (Oxf). 1993;  39 369-374
• 8 Valenzuela G J, Craig J, Bernhardt M D, Holland M L. Placental passage of the oxytocin antagonist atosiban.  Am J Obstet Gynecol. 1995;  172 (4 Pt 1) 1304-1306
• 9 Rasmussen B B, Larsen L S, Senderovitz T. Pharmacokinetic interaction studies of atosiban with labetalol or betamethasone in healthy female volunteers.  BJOG. 2005;  112 1492-1499
• 10 eMC. Tractocile 7.5 mg/ml solution for injection. Available at: http://www.medicines.org.uk/EMC/medicine/4297/SPC/Tractocile+7.5+mg+ml+Solution+for+Injection/ Accessed June 24, 2010
• 11 eMC. Tractocile 7.5 mg/ml concentrate for solution for infusion. Available at: http://www.medicines.org.uk/EMC/medicine/4305/SPC/Tractocile+7.5+mg+ml+Concentrate+for+Solution+for+Infusion/ Accessed June 24, 2010
• 12 UKMi. New medicines on the market. Available at: http://www.ukmi.nhs.uk/NewMaterial/html/docs/atosiban.pdf Accessed June 24, 2010
• 13 Kashanian M, Akbarian A R, Soltanzadeh M. Atosiban and nifedipin for the treatment of preterm labor.  Int J Gynaecol Obstet. 2005;  91 10-14
• 14 Goodwin T M, Paul R, Silver H et al.. The effect of the oxytocin antagonist atosiban on preterm uterine activity in the human.  Am J Obstet Gynecol. 1994;  170 474-478
• 15 Goodwin T M, Valenzuela G J, Silver H, Creasy G. Atosiban Study Group . Dose ranging study of the oxytocin antagonist atosiban in the treatment of preterm labor.  Obstet Gynecol. 1996;  88 331-336
• 16 Thornton J G. The quality of randomised trials of tocolysis.  BJOG. 2006;  113 (Suppl 3) 93-95
• 17 Romero R, Sibai B M, 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 1173-1183
• 18 Romero R, Sirtori M, Oyarzun E et al.. Infection and labor. V. Prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes.  Am J Obstet Gynecol. 1989;  161 817-824
• 19 Moutquin J M, Sherman D, Cohen H et al.. Double-blind, randomized, controlled trial of atosiban and ritodrine in the treatment of preterm labor: a multicenter effectiveness and safety study.  Am J Obstet Gynecol. 2000;  182 1191-1199
• 20 French/Australian Atosiban Investigators Group . Treatment of preterm labor with the oxytocin antagonist atosiban: a double-blind, randomized, controlled comparison with salbutamol.  Eur J Obstet Gynecol Reprod Biol. 2001;  98 177-185
• 21 European Atosiban Study Group . The oxytocin antagonist atosiban versus the beta-agonist terbutaline in the treatment of preterm labor. A randomized, double-blind, controlled study.  Acta Obstet Gynecol Scand. 2001;  80 413-422
• 22 Worldwide Atosiban versus Beta-agonists Study Group . Effectiveness and safety of the oxytocin antagonist atosiban versus beta-adrenergic agonists in the treatment of preterm labour.  BJOG. 2001;  108 133-142
• 23 Papatsonis D, Flenady V, Cole S, Liley H. Oxytocin receptor antagonists for inhibiting preterm labour.  Cochrane Database Syst Rev. 2005;  (3) CD004452
• 24 Al-Omari W R, Al-Shammaa H B, Al-Tikriti E M, Ahmed K W. Atosiban and nifedipine in acute tocolysis: a comparative study.  Eur J Obstet Gynecol Reprod Biol. 2006;  128 129-134
• 25 Coomarasamy A, Knox E M, Gee H, Song F, Khan K S. Effectiveness of nifedipine versus atosiban for tocolysis in preterm labour: a meta-analysis with an indirect comparison of randomised trials.  BJOG. 2003;  110 1045-1049
• 26 Kim A, Shim J Y. Emerging tocolytics for maintenance therapy of preterm labour: oxytocin antagonists and calcium channel blockers.  BJOG. 2006;  113 (Suppl 3) 113-115
• 27 Thornton J G. Maintenance tocolysis.  BJOG. 2005;  112 (Suppl 1) 118-121
• 28 Norwitz E R, Bahtiyar M O, Sibai B M. Defining standards of care in maternal-fetal medicine.  Am J Obstet Gynecol. 2004;  191 1491-1496
• 29 Valenzuela G J, Sanchez-Ramos L, Romero R et al.. Maintenance treatment of preterm labor with the oxytocin antagonist atosiban. The Atosiban PTL-098 Study Group.  Am J Obstet Gynecol. 2000;  182 1184-1190
• 30 Papatsonis D, Flenady V, Liley H. Maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour.  Cochrane Database Syst Rev. 2009;  (1) CD005938
• 31 Helmer H, Brunbauer M, Rohrmeister K. Exploring the role of Tractocile in everyday clinical practice.  BJOG. 2003;  110 (Suppl 20) 113-115
• 32 Goodwin T M, Valenzuela G, Silver H, Hayashi R, Creasy G W, Lane R. Treatment of preterm labor with the oxytocin antagonist atosiban.  Am J Perinatol. 1996;  13 143-146
• 33 Lurie S, Sadan O, Ben Aroya Z, Glezerman M. Atosiban treatment for uterine hyperactivity during active labor: a pilot study.  J Perinat Med. 2004;  32 137-139
• 34 Afschar P, Schöll W, Bader A, Bauer M, Winter R. A prospective randomised trial of atosiban versus hexoprenaline for acute tocolysis and intrauterine resuscitation.  BJOG. 2004;  111 316-318
• 35 de Heus R, Mulder E J, Derks J B, Kurver P H, van Wolfswinkel L, Visser G H. A prospective randomized trial of acute tocolysis in term labour with atosiban or ritodrine.  Eur J Obstet Gynecol Reprod Biol. 2008;  139 139-145
• 36 Fuchs A R, Fuchs F, Husslein P, Soloff M S, Fernström M J. Oxytocin receptors and human parturition: a dual role for oxytocin in the initiation of labor.  Science. 1982;  215 1396-1398
• 37 Fuchs A R, Fuchs F, Husslein P, Soloff M S. Oxytocin receptors in the human uterus during pregnancy and parturition.  Am J Obstet Gynecol. 1984;  150 734-741
• 38 Richter O N, Dorn C, van de Vondel P, Ulrich U, Schmolling J. Tocolysis with atosiban: experience in the management of premature labor before 24 weeks of pregnancy.  Arch Gynecol Obstet. 2005;  272 26-30
• 39 Husslein P, Quartarolo J P. Review of clinical experience with atosiban and the Tractocile Efficacy Assessment Survey in Europe (TREASURE) study protocol.  Int J Clin Pract. 2003;  57 121-127
• 40 Husslein P, Roura L C, Dudenhausen J TREASURE study group et al. Clinical practice evaluation of atosiban in preterm labour management in six European countries.  BJOG. 2006;  113 (Suppl 3) 105-110
• 41 Treschan T A, Peters J. The vasopressin system: physiology and clinical strategies.  Anesthesiology. 2006;  105 599-612 quiz 639-640
• 42 Tsatsaris V, Carbonne B, Cabrol D. Atosiban for preterm labour.  Drugs. 2004;  64 375-382
• 43 Thornton S. Oxytocin receptor antagonists for inhibiting preterm labour. Available at: http://www.cochranefeedback.com/cf/cda/citation.do?id=9535#9535 Accessed June 24, 2010
• 44 Food and Drug Administration .Antocin, (atosiban injection) for use in the management of preterm labor. Gaithersburg, MD: Centre for Drug Evaluation and Research, Advisory Committee for Reproductive Health Drugs; April 20, 1998. Issue-NDA 20–797 83-85
• 45 Food and Drug Administration .Antocin, (atosiban injection) for use in the management of preterm labor. Gaithersburg, MD: Centre for Drug Evaluation and Research, Advisory Committee for Reproductive Health Drugs; April 20, 1998. Issue-NDA 20–797 24
• 46 Papatsonis D N, Kok J H, van Geijn H P, Bleker O P, Adèr H J, Dekker G A. Neonatal effects of nifedipine and ritodrine for preterm labor.  Obstet Gynecol. 2000;  95 477-481
• 47 Papatsonis D N, Van Geijn H P, Adèr H J, Lange F M, Bleker O P, Dekker G A. Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial.  Obstet Gynecol. 1997;  90 230-234
• 48 Goodwin T MRH, Perry K, Menard M K et al.. A report on infant outcomes up to 24 months of age after the use of atosiban in the management of preterm labour. Abstract presented at: 46th ACOG Annual Meeting May 9–13, 1998. New Orleans, LA;
• 49 Akerlund M, Bossmar T, Brouard R et al.. Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women.  Br J Obstet Gynaecol. 1999;  106 1047-1053
• 50 Pierzynski P, Lemancewicz A, Reinheimer T, Akerlund M, Laudanski T. Inhibitory effect of barusiban and atosiban on oxytocin-induced contractions of myometrium from preterm and term pregnant women.  J Soc Gynecol Investig. 2004;  11 384-387
• 51 Reinheimer T M, Bee W H, Resendez J C, Meyer J K, Haluska G J, Chellman G J. Barusiban, a new highly potent and long-acting oxytocin antagonist: pharmacokinetic and pharmacodynamic comparison with atosiban in a cynomolgus monkey model of preterm labor.  J Clin Endocrinol Metab. 2005;  90 2275-2281
• 52 Thornton S, Goodwin T M, Greisen G, Hedegaard M, Arce J C. The effect of barusiban, a selective oxytocin antagonist, in threatened preterm labor at late gestational age: a randomized, double-blind, placebo-controlled trial.  Am J Obstet Gynecol. 2009;  200 627 e1-e10
• 53 Reinheimer T M. Barusiban suppresses oxytocin-induced preterm labour in non-human primates.  BMC Pregnancy Childbirth. 2007;  7 (Suppl 1) S15
• 54 Wilson R J, Allen M J, Nandi M, Giles H, Thornton S. Spontaneous contractions of myometrium from humans, non-human primate and rodents are sensitive to selective oxytocin receptor antagonism in vitro.  BJOG. 2001;  108 960-966
• 55 Steinwall M, Bossmar T, Gaud C, Akerlund M. Inhibitory effects of SR 49059 on oxytocin-and vasopressin-induced uterine contractions in non-pregnant women.  Acta Obstet Gynecol Scand. 2004;  83 12-18
• 56 Steinwall M, Bossmar T, Brouard R et al.. The effect of relcovaptan (SR 49059), an orally active vasopressin V1a receptor antagonist, on uterine contractions in preterm labor.  Gynecol Endocrinol. 2005;  20 104-109