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Pharmacological Intervention in Preterm Labour PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/146284 Please be advised that this information was generated on 2021-10-07 and may be subject to change. 4 --. 'HARMACOLLOÒICAUNTERVENTIO N IN ?RESEW\KA]ÍÓ[JT PHARMACOLOGICAL INTERVENTION IN PRETERM LABOUR Dose studies on ritodrine administration C.A.G. HOLLEBOOM Druk: Haveka bv, Alblasserdam I.S.B.N. 90-9009763-5 Thesis Catholic University Nijmegen.- With réf.- With summary in dutch Subject heading: preterm labour/ tocolysis/ ritodrine Financial support for the publication of this thesis by Solvay Pharma bv, Research Fonds Bronovo, Novo Nordisk Farma bv, Schering Nederland bv, Organon Nederland bv, Glaxo Wellcome bv, Ferring bv, Pfizer bv, Wyeth Laboratoria bv and Zeneca bv, is gratefully acknowledged. Cover illustration: Roses; flowers of love, life and birth.* Cover design: Annemieke van Rosmalen * J. Hall. Dictionary of subjects and symbols in art. New York, 1979. PHARMACOLOGICAL INTERVENTION IN PRETERM LABOUR Dose studies on ritodrine administration een wetenschappelijke proeve op het gebied van de Medische Wetenschappen Proefschrift ter verkrijging van de graad van doctor aan de Katholieke Universiteit Nijmegen, volgens besluit van het College van Decanen in het openbaar te verdedigen op dinsdag 26 november 1996 des namiddags om '3.30 uur precies door Caspar Adriaan Godfried Holleboom geboren op 30 april 1955 te Lubuk Pakan, Indonesië Promotores: Prof. Dr. J.M.W.M. Merkus Prof. Dr. M.J.N.C. Keirse, Flinders University, Adelaide, Australia Manuscriptcommissie: Prof. Dr. H.H.H. Kanhai, Rijks Universiteit Leiden Prof. Dr. G.G.M. Essed, Universiteit Maastricht Dr. H.W. Bruinse, Rijks Universiteit Utrecht Aan Annemieke, Sophie en Jules An optimist is a person who sees a green light everywhere, while a pessimist sees only the red stoplight The truly wise person is colorblind. Albert Schweitzer CONTENTS * Table of Contents 7 * Abbreviations 9 CHAPTER 1 11 * Preterm birth as a perinatal health problem 12 - Preterm birth 12 - Improvements in fetal outcome 12 - Place of tocolytic treatment 12 - Developments in tocolytic treatment 13 - Outline and aims of the thesis 14 CHAPTER 2 17 * Aetiology of preterm labour as a basis for prevention 18 - Introduction 18 - Definitions 18 - Diagnosis of preterm labour 19 - Prediction of preterm labour 20 - Causes of preterm labour and birth 23 - Prevention of preterm birth 25 - Summary 28 CHAPTER 3 31 * Tocolysis 32 - Introduction 32 - Definitions 32 - Tocolytic drugs 32 - Betamimetic agents 32 - Inhibitors of prostaglandin synthesis 40 - Magnesium sulphate 42 - Calcium antagonists 44 - Oxytocin antagonists 45 - Other tocolytic agents 46 - Other pharmacological approaches 47 - Antibiotic treatment 47 - New developments 48 - Prophylactic treatment 48 - General comment 48 CHAPTER 4 51 * A loading-dose infusion scheme for intravenous tocolysis with ritodrine; a pilot study. 52 (Eur J Obstet Gynecol Reprod Biol 1987,26 119-126) CHAPTER 5 61 * A loading model for ritodrine administration in preterm labour. 62 (Br J Obstet Gynaecol 1993,100 1107-1110) CHAPTER 6 69 * Randomized comparison between a loading and incremental dose model for ritodrine administration in preterm labour. 70 (Br J Obstet Gynaecol 1996,103 695-701) CHAPTER 7 81 * Double-blind evaluation of ritodrine sustained release for oral maintenance of tocolysis after active preterm labour. 82 (Br J Obstet Gynaecol 1996,103 702-705) CHAPTER 8 89 * General discussion 90 - Classification of preterm birth 90 - Prevention and early detection of preterm labour 91 - Candidates for tocolysis 92 - Choice of tocolytic treatment 92 - Recommendations for further research 93 * Summary 94 * Samenvatting 98 * References 103 * Appendix 129 - 1) Appendix related to chapter 4 129 - 2) Ritodrine preparation for intravenous administration 131 - 3) Ritodrine dosage schemes 132 - Ritodrine loading dose schedule 132 - Ritodrine intravenous withdrawal schedule 132 * Dankwoord 133 * Curriculum vitae 134 8 ABBREVIATIONS BP Bloodpressure cAMP cyclic Adenosine monophosphate с, Concentration at time t О. Concentration in steady state FIGO Federation International de Obstetrie et Gynaecology FHR Fetal heart rate HPLC High Pressure Liquid Chromatography ID Incremental dose infusion scheme i.v. Intravenous IVH Intraventricular Haemorrhage к Elimination constant LD Loading dose infusion scheme LNMP Last normal menstrual period MLCK Myosin Light Chain Kinase MHR Maternal heart rate Pia Placebo PROM Prelabour rupture of membranes PPROM Preterm prelabour rupture of membranes PP Pulse pressure R Infusion rate RIA Radio Immuno Assay Rit Ritodrine SD Standard deviation SEM Standard error of the mean t Time t,/2 Half life time * 2аш Cumulation half life time tl/2el Elimination half life time Volume of distribution vd 9 10 CHAPTER 1 PRETERM BIRTH AS A PERINATAL HEALTH PROBLEM и Chapter 1 PRETERM BIRTH AS A PERINATAL HEALTH PROBLEM PRETERM BIRTH Preterm birth is the most important factor associated with perinatal morbidity and morta­ lity, contributing to 50-70% of the total neonatal mortality in developed countries (Rush et al. 1976). Strategies aimed at reducing the incidence of preterm birth mainly focus on the prevention of preterm labour by reducing the effects of risk factors or disease, and in addi­ tion, on the inhibition of uterine contractions (tocolysis) once the preterm labour process has begun. Despite these preventive and treatment strategies, preterm birth rates have remained relatively stable over the past 10-20 years in developed countries: varying from 4-10% of all births (Lumley 1993). IMPROVEMENTS OF FETAL OUTCOME The boundary of viability for a live birth infant is about 24 weeks of gestation, after which paediatric intervention may benefit survival although with a major risk on serious disabi­ lity (Hack and Fanaroff 1989, Hack et al 1991, Rutter 1995, Lefebvre et al. 1996). Copper et al.(1993) reported from 5 major institutions in the United States (1982-1986), a survival rate of 9.9% at 24 weeks of gestation, which survival rate increased to 77.4% at 28 weeks, 96.5% at 32 weeks and 99.5% at 36 weeks. The greatest weekly increase (from 15.5% to 54.7%) occurred between weeks 25 and 26. Even better results are published by Fanaroff et al. (1995) from 12 participating centres of the National Institute of Child Health and Human Development Neonatal Research Network (1991-1992) in the United States, with a survi­ val rate of 47% at 24 weeks, 68% at 25 and 83% at 26 weeks. The biggest contribution to neonatal morbidity is foremost caused by the respirato­ ry distress syndrome, necrotising enterocolitis, intra- and peri-ventricular haemorrhage, persistent fetal circulation and sepsis (Robertson et al. 1992, Fanaroff et al. 1995, Rutter 1995). The incidence of these morbidities declines with increasing gestational age and birthweight (Robertson et al. 1992, Fanaroff et al. 1995). Furthermore antenatal corticosteroids administration, improved peripartum management and neonatal intensive care nursing and exogenous surfactant therapy have all contributed to improved neonatal outcome (Fanaroff et al. 1995). PLACE OF TOCOLYTIC TREATMENT The major improvements in neonatal outcome have been derived from advances in neo­ natology and perinatal care and little can be attributed to the prevention of preterm birth (Keirse et al. 1989). An explanation for this disappointing fact is that a minor part of patients with preterm labour are suitable candidates for tocolytic treatment (Rush et al. 1976, Tucker et al. 1991, Villar et al. 1994). Only one-third of preterm births result from pre­ term labour uncomplicated by fetal or maternal pathology and only a fraction of these qualify for tocolytic treatment (Keirse and Kanhai 1981). The presently available tocolytic agents are capable in delaying threatening preterm delivery with 24-48 hours (betamimetics) and 7-10 days (indomethacin) but do not reduce 12 PRETERM BIRTH AS A PERINATAL HEALTH PROBLEM the incidence of preterm birth (Keirse et al. 1989). Nevertheless tocolytic treatment aimed to postpone imminent preterm delivery may attribute to fetal well-being by gaining time, which in itself improves perinatal outcome. Furthermore this time gain makes it possible to administer corticosteroids with their positive effect on fetal (lung) maturation (Crowley et al. 1990, Crowley3 1995) and, if necessary, to antepartum transport to an appropriate perinatal health centre (Verloove-Vanhorick et al. 1988, Lamont et al. 1983). The time gain obtained by using tocolytics in extremely preterm labour (<28 weeks), albeit short, may in itself attribute to a distinct increase in survival rate, especially between 25 and 26 weeks of gestation (Goldenberg et al. 1984, Copper et al. 1993, Fanaroff et al. 1995). DEVELOPMENT IN TOCOLYTIC TREATMENT New drugs Introduction of new tocolytic agents such as calcium-blockers, Nifedipine (Andersson 1987, Ulmsten et al. 1980), oxytocin antagonists, Atosiban (Àkerlund et al. 1987) and prosta­ glandin synthesis inhibitors, Sulindac (Carian et al. 1992) seems promising. Before appli­ cation in clinical practice, randomized trials should be performed with these drugs to con­ firm the positive preliminary findings and to asses their value in the treatment of preterm labour. Experimental drugs There is increasing evidence that infection and the subsequent immune response plays a crucial role in the
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