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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 initiating of preterm labour (Lopez Bernal et al. 1993). Cytokines, like interleukin-1 (IL-1) and tumour necrosis factor (TNF), may initiate uterine contraction by there influence on the prostaglandin production (Challis and Mitchell 1994). Recently a IL- 1 receptor antagonist has been developed which, in an in vitro experimental model (Romero and Tartakovsky 1992), reduces the prostaglandin E2 production in human amnion and chorion. To date, no clinical results are available. Other experimental developments involve the search to a collagenase inhibitor, cytokine synthesis inhibitor factor (IL-10) and prostaglandin synthesis inhibitors acting on the cyclo-oxygenase-2 enzyme.

Dose regimens for betamimetics

Dose studies have been performed with betamimetics to develop other regimens of drug administration to prevent the well known tachyphylaxis and loss of drug effectiveness by continuous administration, which is probably caused by down-regulation of receptors (Berg et al. 1985, Casper and Leye 1986, Caritis et al. 1987). Studies with pulsatile or bolus administration and micro-injections of betamimetics, to overcome this latter effect, have shown that such approaches might allow inhibition of uterine activity with a lower total dose of drug than the traditional infusion regimens with betami-metics (Caritis et al 1991, Ke et al. 1984, Lam et al. 1995). Application of a pulsatile regimen of betamimetics subcutaneously is also likely to reduce the incidence, duration and severity of side effects, although reports are not always con­ sistent (Stubblefield and Heyl 1982, Spätling et al. 1989, Caritis et al. 1991, Lam et al. 1995, Ke et al. 1984).

13 Chapter 1

The degree and severity of betamimetic induced side effects relates not only to the plasma concentration and infusion rate but also to changes in them (Caritis et al. 1983, 1984). The originally advised incremental dosage scheme for intravenous tocolysis (Barden et al. 1980) needs many changes in infusion rate and results in a gradual increase in plas­ ma concentrations above the concentration needed for maintaining uterine quiescence (Smit et al. 1984). This makes investigations to determine the optimum dose regimens for betamimetics still actual (Ingels et al. 1985, Holleboom et al. 1987,1993, Caritis et al. 1990). Oral maintenance of tocolysis with betamimetics in the refractory period after arresting preterm labour may decrease recurrence rate of preterm labour, albeit preterm birth rate is not reduced (Keirse et al. 1989). Preventing re-infusion and re-admission is worthwhile in terms of reduction in costs of hospitalisation and social discomfort. To over­ come the disadvantage of frequent drug intake (up to six times day and night!), due to low bioavailability and short halve life times of betamimetics, a sustained release formula, reducing intake to three times daily, has been introduced (Essed et al. 1987,1988). No data on its efficacy in preventing recurrence of preterm labour are available to date.

OUTLINE AND AIMS OF THE THESIS

The thesis consists of two parts. In the first part a review of literature is given. Chapter 2 deals with the aetiology of preterm labour and various predictive and preventive meas­ urements in the treatment of preterm labour and chapter 3 comments on currently availa­ ble tocolytic drugs. The second part describes the several chronological studies to deter­ mine the best way of intravenous ritodrine loading administration in the treatment of pre­ term labour. Also studied is the value of ritodrine sustained release capsules as oral main­ tenance.

The aims of this thesis were to answer the following questions: 1) Will a loading dose infusion scheme for intravenous tocolysis with ritodrine, based on the ritodrine elimination half-life time, maintain stable ritodrine plasma concen­ trations once the infusion rate has been reduced when uterine quiescence is achieved? 2) Can a loading dose infusion scheme for ritodrine administration in preterm labour, based on the ritodrine cumulation halve-life time, avoid plasma concentrations above those needed for tocolysis? 3) What is the influence of the loading dose infusion scheme on the amount of dose adjustments? 4) Is the loading dose infusion scheme easily applicable in clinical practice? 5) What are the advantages of the new loading dose regimen compared with the con­ ventional incremental dose regimen for ritodrine administration in the treatment of preterm labour? 6) Is it possible, by administration of ritodrine sustained release capsules to maintain uterine quiescence and to reduce the recurrence rate of preterm labour and /or to prolong the recurrence free interval after initial successful arrest of preterm labour?

Answer on the first question will be given in chapter 4, which describes the development of a loading dose infusion scheme with its pharmacokinetic backgrounds and first appli­ cation in a pilot study. Answers on the second question and partly on the third and fourth question will be given in chapter 5 where the adapted loading dose infusion scheme is tes­ ted. Plasma concentrations at the moment of tocolysis and in the steady state period are

14 PRETERM BIRTH AS A PERINATAL HEALTH PROBLEM compared with each other and with expected calculated plasma concentrations. General acceptance of the scheme and the rate of dose adjustments is scored. In chapter 6 a ran­ domized multi centre trial of ritodrine administration by loading or incremental dose sche­ me in preterm labour is presented which will answer question three, four and five. The six question is answered in chapter 7 by a double blind evaluation of ritodrine sustained re­ lease capsules versus placebo administered after active preterm labour. Chapter 8 contains a general discussion of the results. 16 AETIOLOGY OF PRETERM LABOUR AS A BASIS FOR PREVENTION Chapter 2 AETIOLOGY OF PRETERM LABOUR AS A BASIS FOR PREVENTION

INTRODUCTION

In the last few years many studies have indicated that preterm labour/birth is a multifac­ torial condition, rather than a disorder with a multitude of independent causes (Creasy 1993). Despite the implementation of many preventive programmes, risk intervention stra­ tegies and the development of new tocolytic drugs, preterm birth is still the leading cause of perinatal morbidity and mortality. The incidence of preterm birth is 8-10% in the USA, Africa, Asia and the former USSR; around 7-8% in Latin America and between 4% and 7% in Europe (Villar et al. 1994, Lumley 1993, Creasy 1993). This accounts yearly for a total of 13 million preterm births worldwide of which 90% in developing countries (Villar et al. 1994).

DEFINITIONS

Not all preterm babies have similar morbidity and mortality risks. Before 29 weeks gesta­ tional age is the best predictor of survival, whereas, birthweight tends to be more impor­ tant later in gestation (Robertson et al. 1992, Copper et al. 1993, Lefebvre et al. 1996). Survival exceeds 90% after 30 completed weeks of pregnancy; intraventricular haemor­ rhage declines by 27 weeks and is rarely seen after 32 weeks; the incidences of persistent fetal circulation and necrotizing enterocolitis decrease rapidly after 32 weeks. The inciden­ ce of respiratory distress syndrome, the most frequent cause of morbidity in preterm infants, is 80-90% at 25-27 weeks, but it falls to less than 3.5% in preterm infants at 36 weeks (Copper et al. 1993, Fanaroff et al. 1995). Advances in perinatal care can be obtained in the very young preterm infant by delaying birth by a few days, whereas this will hardly have any effect at all on the outcome of babies born after 34 weeks of gestation (Goldenberg et al. 1984).

Table 1 Official definition (WHO) and proposed subdivisions of preterm birth (Keirsea 1995, Lumley 1993).

WHO:

* preterm birth: birth before 37 completed gestational weeks or less than 259 days after the first day of the last normal menstrual period (LNMP).

SUBDIVISIONS:

* mildly preterm: birth between 32 and 36 weeks of gestation * very preterm: birth before 32 weeks of gestation * extremely preterm: birth before 28 weeks of gestation

18 AETIOLOGY OF PRETERM LABOUR AS A BASIS FOR PREVEbTTION

Therefore, it seems important to make subdivisions in preterm birth if we wish to evaluate the results and impact of different treatment strategies in preventing either preterm labour or preterm birth (see table 1). This is in analogy with commonly accepted subdivisions in birthweight; such as low birthweight < 2500 gram, very low birthweight < 1500 gram, and extremely low birthweight < 1000 gram).

Of all preterm births 10% is extremely preterm, 10-15% is very preterm, and the majority (75-80%) mildly preterm (Lumley 1993). Two-thirds of deaths related to preterm births occur in infants bom before the 32 week of gestational age; i.e. in very to extremely pre­ term infants (Heinonen et al. 1988).

DIAGNOSIS OF PRETERM LABOUR

The diagnosis preterm labour is so difficult that probably 30- 40% of women admitted for this reason are not really in labour (Kragt and Keirse 1990, Kragt 1991). Labour is usually defined as the presence of regular and frequent uterine contractions leading to progressive dilatation of the cervix and to delivery. In preterm labour the last two criteria, progressive dilatation and delivery, are the one's we try to prevent. Effective treatment leading to delay of delivery and prolongation of pregnancy after 37 weeks of gestation is in contradiction with earlier diagnosis of preterm labour. The inaccuracy of the early diagnosis of preterm labour is confirmed by the high success rates of placebo treatments in prolonging preg­ nancy and delaying delivery (King et al. 1988). In general, the diagnosis of preterm labour is initially made by the woman herself and adopted or withdrawn by her attendants. The view that women are not well able to diagnose preterm labour and are mistaken in 80% of their diagnoses (O'Driscoll 1977) was not confirmed by Kragt and Keirse (1990) who found that 75% of women were right in the idea that something was seriously wrong and that hospitalisation was warranted. When the patient was confused about wether or not she was in preterm labour, there was a good change that initially the clinician was also mis­ taken, and that he or she needed 48 hours to clarify the diagnosis. Signs and symptoms occurring statistically more frequent in women in preterm labour compared with controls are: increased uterine contractions, menstrual cramps, con­ stant backache, constant pelvic pressure, increased amount and consistency and colour change of vaginal discharge, and increased frequency of urination (Katz et al. 1990). In the study done by Katz et al. (1990) only 2 out of 100 patients with confirmed pre­ term labour did not report any of the above mentioned symptoms. Interestingly, 29% of patients in confirmed preterm labour did not report any contraction, 19% reported neither contractions nor menstrual-like cramps, and 15% reported no contractions, menstrual-like cramps, or abdominal intestinal cramps. Only halve of the patients in confirmed preterm labour found contractions painful; and the frequency of contractions was in 50% of the women less than one every 10 minutes. Although the positive predictive value of these symptoms was high (>85%), the sensitivity, except for contractions (71%), was quite low (<45%) making them not accurate to distinguish between true and false preterm labour (Katz et al. 1990). The absolute frequency of uterine contractions appears to be of less importance as far as the effect of uterine activity on the cervix is concerned. Even with regular, but infrequent contractions (6-12 min apart) cervical changes may occur. The fre­ quency of contractions less than every 5 minutes was found in 25-40% of patients with documented preterm labour (Martin et al. 1990, lams et al. 1990).

19 Chapter 2

PREDICTION OF PRETERM BIRTH

Clinical parameters and biochemical tests

To improve the accuracy of the prediction of preterm birth many clinical parameters have been introduced, such as serial cervical examinations manually (Papiernik et al. 1986, Leveno et al. 1986) or by ultrasound (Andersen et al. 1990, lams et al. 1994, Gomez et al. 1994), antenatal monitoring of uterine contractions (Bell 1983, Nageotte et al. 1988, Newman et al. 1990, Rhoades et al. 1991), assessments of fetal breathing movements by ultrasound (Besinger et al. 1987, Boylan et al. 1985, Agustsson and Patel 1987). Also many biochemical tests have been introduced including measurement of hormone levels (Tamby Raya et al. 1971, Cousins et al. 1977, Smit" et al. 1984, Jackson et al. 1995, Mazor et al. 1994), prostaglandin metabolites (Fuchs et al. 1982, Weitz et al. 1986), urinary thromboxane excre­ tion (Noort et al. 1988), and the detection of bioactive compounds normally produced by mechanical damage or in the presence of inflammation, such as fetal fibronectin in cervi­ cal mucus (Lockwood et al, 1991, Nageotte et al. 1994), interleukin-6 (IL-6) in amniotic fluid (Romero et al. 1990), tumour necrosis factor (TNF) and IL-6 in cervical mucus (Lockwood et al. 1994, Inglis et al. 1994), and placental corticotrophin releasing hormone (CRH) in maternal serum (Wolfe et al. 1990, Warren et al. 1992). Most of these tests are not easily applicable to predict preterm labour in routine screening programmes for preterm labour because of their moderate to low sensitivity and poor predictive value (McLean et al. 1993). In high risk pregnancy populations these tests might be of value in predicting preterm labour. Most promising in this respect are the results obtained with fetal fibronectin in cervicovaginal secretions.

Fetal fibronectin

Fetal fibronectin is a component of the extracelluar matrix and plays a role in the chorio­ nic-decidual interface; preterm labour may disrupt the cell attachment properties of fibro­ nectin, allowing fibronectin to leak into cervicovaginal secretions. Initially, Lockwood et al. (1991) found cervicovaginal fetal fibronectin present in 50% of women with preterm contractions. In their population the prediction of preterm birth with a positive test had a sensitivity of 81.7% and a specificity of 82.5%. However, in an asymptomatic population of innercity women, 4 weekly cervical assessment of fetal fibronectin a positive test predicted only one third of cases of preterm contractions and one fourth of preterm births (Lockwood et al. 1993). In contrast, Nageotte et al. (1994) tested 102 asymptomatic women at high risk for preterm birth weekly for fetal fibronectin and showed a prediction of preterm birth with a sensitivity of 93%, a specificity of 92%, a posi­ tive predictive value of 46% and a negative predictive value of 94%. In a low risk popula­ tion (n=133), Hellemans et al. (1995) found with 2 weekly cervical assessment of fetal fibro­ nectin a prediction for preterm birth of 25% with a sensitivity of 60%, a specificity of 85%, and a negative predictive value of 96%. Leeson et al. (1996) described a positive predictive value for preterm birth of 50% with 2 weekly screening in a high risk population (n=43); sensitivity was 17%, specificity 93% and the negative predictive value 73%. In general, the cervicovaginal fibronectin test, may improve our diagnostic possibi­ lities and may lead to earlier better detection of high risk patients. Until now this test is of limited value in screening general or low risk populations.

20 AETIOLOGY OF PRETERM LABOUR AS A BASIS FOR PREVEmiON

Formal risk scoring

Another way of trying to predict preterm birth, in the absence of other markers of preterm labour, is the use of risk factor scoring systems (Papiernik et al. 1974, Kaminski et al. 1974, Creasy et al. 1980). These systems consist of weighted factors reflecting socioeconomic sta­ tus, medical history, daily habits, and current pregnancy problems that are associated with preterm labour (see table 2). The high risk population identified by this risk factor scoring then can receive special medical attention and educational programmes in order to prevent preterm labour. The most widely used scoring system is that of Creasy et al. (1980), which is a modification of the risk factor scoring system designed by Papiernik (Papiernik and Kaminski 1974). It is relatively easy to apply (see table 3). A total score of >10 points is con­ sidered indicative of a high risk of preterm birth. An analysis of several studies using the risk scoring system of Creasy reveals that the sensitivity is poor (<50%) and that the posi­ tive predictive value lays between 17 and 38% (Keirse 1989, McLean et al. 1993, Strobino 1993). This means that only half of the women who actually deliver preterm are identified and that 60 to 80% of the women who are thought to be at increased risk do not deliver preterm!

Table 2 Risk factors associated with preterm birth demographic and psychosocial f actors preterm rupture of membranes lower social class late or no antenatal care black race advanced cervical dilatation unmarried status preeclampsia or eclampsia low maternal age hyperemesis fewer than 12 years of education polyhydramnios low pregravid weight isoimmunisation stress placenta praevia standing for prolonged periods placental abruption prolonged strenuous work multiple pregnancy short stature fetal congenital malformations obstetric factors maternal morbidity during pregnancy in previous pregnancies anaemia previous fetal or neonatal death cervical colonisation with: Chlamydia, group previous spontaneous abortion or preterm В Streptococcus, Neisseria gonorrhoea delivery trauma cervical incompetence surgery maternal genital abnormality anaesthesia maternal in utero exposure to DES hyperthyroidism previous placenta praevia nephritis previous preterm rupture of membranes pyelonephritis short pregnancy interval Uver disease in current pregnancy pulmonary disease and viral pneumonia preterm labour chronic hypertension

Adapted from Witter (1993)

21 Chapter 2

This group will be exposed to an intervention programme that not only gives unnecessa­ ry emotional stress but is also likely to be expensive, hazardous, or both, because the inter­ vention programmes usually use hospitalisation, tocolysis, cervical cerclage, etc. Analysis of the risk scoring systems shows that a high influence is attributed to a history of preterm delivery. This single factor receives 10 points and places the patient automatically at high risk. In Primigravidae there can be no such history, nevertheless these women account for 50% of all preterm deliveries which explains the low sensitivity of the scoring at least in primigrávida. Nowadays, risk scoring systems are no longer wide­ ly used because they are not discriminating enough in order to start therapeutic ap­ proaches toward the problem of preterm labour (Creasy 1991). In clinical practice the implementation of these scoring systems has not been shown to convey more benefit than harm to the women and infants involved (Keirse* 1989). Even in populations with a high preterm delivery rate the risk scoring system failed to predict preterm delivery reliably (Main et al. 1987).

Table 3 Risk of Preterm Delivery' (Creasy et al. 1980)

Points Socioeconomic status Past history Daily habits Current pregnancy

2 children at home 1 abortion Work outside home Unusual fatigue Low socioeconomic <1 year since status last birth

Younger than 20 years 2 abortion More than 10 ag Less than 13 kg gain Older than 40 years per day by 32 weeks'gestation Single parent Albuminuria Hypertension Bacterium

Very low socioeconomic 3 abortions Heavy work Breech at 32 weeks status Long bring trip Weight loss of 2 kg Shorter than 150 cm Head engaged Lighter than 45 kg Febrile illness

Younger than 18 years Pyelonephritis Metrorrhagia after 12 weeks'gestabon Effacement Dilation Uterine irritability

Uterine anomaly Placenta praevia Second trimester abortion Polyhydramnios DES exposure

10 Preterm delivery Twins Repeated second trimester Abdominal surgery abortion

'Score is computed by adding the number of points given Totals of 0-5 indicate low risk, 6-9 medium risk, and more than 10 high risk.

22 AETIOLOGY OF PRETERM LABOUR AS A BASIS FOR PREVENUON

CAUSES OF PRETERM LABOUR AND BIRTH

Preterm labour and delivery have a very complex and heterogenous aetiology. In general three major subdivisions in the aetiologic pathway of preterm birth are encountered in lite­ rature (Savitz et al. 1991, Villar et al. 1994 ):

1. Spontaneous "idiopathic" preterm labour.

2. Preterm prelabour rupture of membranes (pprom).

3. Medically indicated or "iatrogenic" preterm birth.

Spontaneous "idiopathic" preterm labour

Definition: labour starting without apparent reason before rupture of membranes, resulting in preterm delivery.

This category of spontaneous preterm labour implies that the aetiology of the preterm labour is not known upon admission of the patient. Secure analysis of 50 patients with spontaneous "idiopathic" preterm labour and birth by careful review of the history and physical examination, antepartum targeted ultrasonography, amniocentesis for Gram stain­ ing, culture and glucose determination, laboratory analysis for infection and for autoim­ mune disease (ANF, lupus anticoagulant, anticardiolipine antibody), as well as postpar­ tum histologic examination of the placenta revealed that the cause of preterm birth remain­ ed idiopathic in only 2 patients (4%) (Lettieri et al. 1993). In all other cases one or more factors were found that in the opinion of the authors could explain the cause of the pre­ term labour process. Of these the most frequent were: faulty placentation (placental abrup­ tion, placenta previa) in 50%, intra-uterine infection in 38%, and immunologic factors in 30% (Lettieri et al. 1993). It has to be questioned if the abnormalities found are the true explanations and causes of the preterm birth process. On the other hand it illustrates the problems in diagnosis and definition in this area. It has been argued that the term idio­ pathic, implying that there is no external or reasonable cause, would seem to be no longer appropriate, especially because it tends to hamper rather than stimulate the search for its cause (Keirsea 1995). In a tabulation of 12 studies, spontaneous preterm labour seems to be predominant in lower-risk white populations and accounts for 27.9-64.1% of all preterm deliveries (Savitz et al. 1991). Meis et al. (1995) found a strong association between spontaneous pre­ term birth and young maternal age, low maternal weight, low or high parity, previous abortion, smoking and early pregnancy bleeding. However, they combined preterm pre­ labour rupture of membranes within their spontaneous preterm delivery population, and this population accounted for 62.6% of all preterm births. In a study on fetal growth and preterm delivery published by Hediger et al. (1995) spontaneous preterm labour was the principal cause in 47.8% of all preterm births. The babies born in this group and those born after PPROM tended to be proportionally or symmetrically smaller than the control group, which suggested a pattern of altered fetal growth that may have its origins early in preg­ nancy or may possibly reflect more chronic "stress". Babies born after medically indicated preterm delivery had a asymmetric growth retardation reflecting late placental insuffi-

23 Chapter 2 ciency. Because this study started intake at 32 weeks of gestation no results were obtained about very and extremely preterm births. In a Danish retrospective study (Kristensen et al. 1995) idiopathic preterm birth was associated with emergency caesarean delivery at term in previous pregnancies and with infants of lower birthweight in previous and subsequent pregnancies.

Preterm prelabour rupture of membranes (PPROM)

Definition: rupture of membranes occurring before 37 completed weeks at least one hour before the onset of uterine contractions.

PPROM complicates 1% to 2% of all pregnancies (Gibbs and Blanco 1982). In the study of Savitz et al. (1991) PPROM accounted for 7.1-51.2% of all preterm births and black women had a markedly higher risk of preterm delivery mediated especially by PPROM. Hediger et al. (1995) found a total frequency of 34.8% for PPROM in all preterm births and a same sym­ metrically growth retardation of the newborn as observed in spontaneous preterm labour. The cause of PPROM remains unknown in most cases. The composition and the amount of collagen as well as the structural quality of the amnion and chorion may play an important role (Al-Zaid et al. 1980, Bou-Resli et al. 1981). Many predisposing factors have been proposed (see table 4), including factors, such as incompetent cervix, chorioam- nionitis, bac-terial vaginosis, multiple gestation and trauma (Hadley et al. 1990, Naeye et al. 1980, Gravett et al. 1986) There seems to be no association between sexual intercourse and the risk of PPROM and preterm birth (Mills et al. 1981, Kurki et al. 1993).

Table 4 Proposed aetiologies and associations with preterm prelabour rupture of membranes

Incompetent cervix Iatrogenic causes Amniocentesis Cervical cerclage Uterine overdistension Multiple gestation Polyhydramnios Membrane weakness Bacterial infection Unknown

Adapted from Christmas (1993)

There is now strong evidence that implicates infection as a cause of preterm labour and delivery, especially in PPROM, although it is clearly not the only cause (Lamont and Fisk 1993, McCoy et al. 1995). Since Minkhoff et al. (1984) reported a positive association between PPROM and infection with Trichomonas vaginalis and colonisation with Bacteroides species, others have found a similar association between PPROM and Neisseria Gonorrhoea, Chlamydia Trachomatis, group В streptococci and bacterial vagi­ nosis (Miller and Pastorek 1986, Newton and Clark 1988, Alger et al. 1988, Kurki et al.

24 AETIOLOGY OF PRETERM LABOUR AS A BASIS FOR PREVENTION

1992, Gibbs et al. 1992, Hay et al. 1994). The way of action by which infection causes PPROM and preterm labour is membrane weakening due to bacterial proteases (McGregor et al. 1987) and stimulation of the production of prostaglandins (Bennett et al. 1987, Lamont et al. 1990). The prostaglandin production is believed to be mediated by; a) bacte­ rial phospholipase A2 production, an enzyme that liberates arachidonic acid, b) direct invasion of the extraplacental membranes adjacent to the cervical os, leading to disruption of amniotic cells and release of lysosomal enzymes, c) migration of maternal inflammato­ ry cells that do metabolize arachidonic acid, and d) loss of 15-hydroxy-prostaglandin dehydrogenase in the chorion. Several of these processes also activate the cytokine casca­ de and cytokine activity is persistent once started (Challis and Mitchell 1994).

Medically indicated or "iatrogenic" preterm birth

Definition: Preterm birth directly related to severe pregnancy complications (fetal/matern­ al pathology)

It is important to subdivide the medically indicated preterm birth group on the basis of dif­ ferences in etiological background. Medically indicated preterm delivery can thus be divided in a group with spontaneous preterm labour in whom associated maternal and/or fetal pathology contraindicates treatment to prolong pregnancy and a group, in which the obstetrician makes the decision to induce labour or to perform caesarean section on basis of pregnancy pathology without signs of preterm labour (Keirse, discussion remark in Villar et al. 1994). The medically indicated preterm delivery population accounts for 18.7% to 35.2% of all preterm births and for 1.1% to 3.7% of all births in the review of Savitz et al. (1991). Meis et al. (1995) in an analysis of the Cardiff Births Survey (1970-1979), found that medically indicated preterm birth was the case in 37.4% of all preterm births and 1.9% of all births from the survey. Medically indicated preterm birth was associated with older age, low weight, previous stillbirth, bacteriuria, and early pregnancy bleeding. Tucker et al. (1991) noted that one-fourth of the preterm births in an indigenous population was iatrogenic due to maternal or fetal conditions requiring delivery. Medical reasons to induce or accept preterm delivery are the well known severe, sometimes, life-threatening pregnancy complications, such as placental abruption, chorio- amnionitis, fetal acquired or congenital diseases, fetal death, placenta praevia, fetal dis­ tress, chronic or pregnancy-induced hypertension, intra-uterine growth retardation, and severe pre-eclampsia.

PREVENTION OF PRETERM BIRTH

Definition: Primary prevention includes all activities and treatment strategies to prevent the initiation of preterm labour (mostly in women at risk of preterm birth), while secon­ dary prevention aims to inhibit the already started preterm labour process.

Primary prevention

The successful prospective identification of a subgroup of pregnancies at increased risk for preterm labour and delivery allows the rational use of interventions aimed at prolonging gestation, be they psychological, social, medical or pharmacological in nature. Several epi-

25 Chapter 2 demiological and obstetric associations are well recognized, including poor socio-econo­ mic status, ethnic group (e.g. black in the USA and Aboriginal in Australia), age <20 or >35 years, primiparity, multiple pregnancy, bleeding during pregnancy, and previous preterm delivery or mid-pregnancy loss (Lumley 1993). The influence of physical activity is not clear­ ly understood but heavy workload and particularly prolonged standing may increase the risk of preterm birth (Colie 1993, Creasy' 1991). As discussed above, risk scoring sys­ tems based on these associations are low both in sensitivity (general < 50%) and in positi­ ve predictive value (17% to 34%), and perform particularly poorly in primigravid women (Keirse 1989', McLean et al. 1993). Home uterine activity monitoring, first reported by Katz et al. (1986), registers ute­ rine contractions in women at high risk for preterm labour and birth. Several authors claimed that home uterine activity monitoring led to early detection of preterm labour and lower rates of preterm birth in high risk patients (Morrison et al. 1987, lams et al. 1987, 1988, Hill et al. 1990, Dyson et al. 1991). In a meta-analysis done by Keirse" (1995) concern was expressed about the quality of the various studies that have been reported. The most recent multicenter randomised trial of home uterine monitoring (n=1355) showed that the availability of home uterine activity monitoring data was not associated with lower rates of preterm birth, higher birth weights or gestational ages, or fewer infant complications at birth in high risk patients compared with high risk patients in whom home uterine activi­ ty monitoring data were not available (The collaborative home uterine monitoring study (CHUMS) group 1995). It has also been suggested that the benefit of home uterine activity monitoring, if any, reflects the consequence of frequent nurse-patient contact. Because home uterine activity monitoring is expensive others have primarily focus­ ed their attention on educational programmes to increase patient and provider awareness of preterm contractions and the importance of early intervention. In a meta-analysis these preterm-birth prevention educational programmes appear to have little benefit in reducing preterm birth and may result in an increased rate of diagnosis of preterm labour (Hueston et al. 1995). The French national programme for reduction of preterm births, which started in 1971, involved an intervention strategy modifying lifestyle to reduce the workload of women, thereby reducing uterine contractions and/or premature maturation of the cervix (Papiernik 1984, Papiernik et al. 1985, Papiernik 1993). The French government allowed pregnant women at risk of preterm delivery payed sickness leave. Preterm deliveries were significantly reduced in France from 7.9% in 1971 to 5.8% in 1981 and 4.1% in 1989. This was associated with a major reduction in very preterm births: 1.6% in 1972, 0.7% in 1981 and 0.5% in 1989. The decrease, however, was predominantly in the groups with low to moderate risk. As this intervention was applied to all pregnant women and not in the con­ text of a controlled trial, it is not possible to demonstrate a causal relationship between the intervention and the observed effects. Infection plays an important role in the aetiology of preterm delivery, especially in preterm prelabour rupture of the membranes (Minkhof et al. 1984, Lamont and Fisk 1993, Meis* et al. 1995). Early treatment of vaginal infection begins with selecting women with asymptomatic bacterial vaginosis, group В streptococci carriers and sexually transmitted diseases. This can be done either by culture or easier and cheaper, by examining a wet swab of vaginal secretions for clue cells, pH and the fishy odour characteristic of bacterial vaginosis (McCoy et al. 1995, Meis' et al. 1995). Morales et al. (1994) demonstrated a signi­ ficant reduction in the incidence of preterm labour, preterm delivery and PPROM with prophylactic metronidazole in a pregnancy population who experienced previous preterm

26 AETIOLOGY ОТ PRETERM LABOUR AS A BASIS TOR PREVEimON delivery complicated by bacterial vaginosis. Treatment of pregnant women with bacterial vaginosis by clindamycin vaginal creme did reduce the incidence of bacterial vaginosis colonisation, but did not statistically significant improve pregnancy outcome (McGregor et al. 1994). Two other randomised blinded trials studied the efficacy of prophylactic admini­ stration of erythromycin in women who were considered to be at increased risk for pre­ term labour on the basis of urogenital Mycoplasmas. They found no evidence that this treatment is effective in reducing preterm labour (McCormack et al.1987, Eschenbach et al. 1991). Also treatment of pregnant women colonized with group В streptococci with ery­ thromycin was not shown to be effective in prolonging gestation or preventing low birth- weight (Klebanoff et al. 1995). On the other hand, antibiotic treatment of asymptomatic bacteriuria reduced the incidence of preterm birth as shown in a meta-analysis of ran­ domised trials (Smani 1995). Further trials are needed to asses the efficacy of prophylactic antibiotic treatment in women at increased risk of preterm delivery due to urogenital bac­ terial colonisation. Prophylactic tocolytic treatment with betamimetics has not been shown to be effec­ tive in preventing preterm labour or preterm birth in patients thougth to be at increased risk of preterm birth (Keirse et al. 1989). 17a-hydroxyprogesterone, administered intramuscularly, showed a significant reduction in the incidence of preterm birth with an odds-ratio of 0.5 and 95% confidence intervals between 0.3 and 0.85 in a meta-analysis of six placebo controlled trials (Keirse et al. 1989, Keirse 1990). There was no evidence that these effects reduced perinatal mortality and morbidity. Interestingly, 17a-hydroxyprogesterone is no longer widely used in clinical practice, probably because of the repeated intramuscular injections. It has been replaced by other (oral) progestogens, but for these there is no evidence of their effectiveness! Cervical incompetence may lead to preterm cervical dilation and maturation with­ out increased uterine activity. It is associated with preterm prelabour rupture of mem­ branes and mid pregnancy loss. Cervical cerclage may reduce the incidence of preterm birth in women with a history of cervical incompetence (Kuhn and Peperell 1977, Maglina et al. 1983), but there is no evidence that cervical cerclage improves outcome in women selected for treatment on the basis of second trimester abortion or preterm birth alone, without such a clear history (Keirse et al. 1978). The MCR/RCOG trial of cervical cerclage (MCR/RCOG 1993) randomized 1292 women with single or multiple pregnancies to recei­ ve elective cerclage or not. There were significantly fewer deliveries before 33 weeks in the cerclage group, particularly when the clinical signs of typical cervical incompetence were considered. Despite this, the overall rate of miscarriage, stillbirth or neonatal death was not statistically significantly different and the use of cervical cerclage was associated with a doubling of the risk of puerperal pyrexia. Similar conclusions were reached from a meta­ analysis of randomised studies investigating cervical cerclage in women with a history of preterm birth or midpregnancy loss (Grant 1995). Cervical cerclage should only be applied in women with a history of cervical incompetence, but a correct diagnosis of this condition is often troublesome. The use of vaginal ultrasound shows promise as a test for cervical competence (lams et al. 1995), but further study is warranted to clarify its place in clinical practice.

Secondary prevention

When the active preterm labour process has already started secondary prevention consist mainly of treatment with tocolytics. These agents will be discussed in the chapter "Tocolysis".

27 Chapter 2

In summary, tocolytics are able to postpone delivery by some days but they cannot prevent preterm delivery and they do not change neonatal morbidity and mortality if used alone. The time gained must be used to administer glucocorticosteroids for fetal (lung) matura­ tion, assessment of fetal well being and if necessary antepartum transport to centres with appropriate perinatal and neonatal facilities. The results of supplementing standard tocolysis with antibiotics has been conflic­ ting. Although Morales et al. (1988) showed a significant prolongation of pregnancy after administration of antibiotics added to tocolytics, Newton et al. (1989) and Romero et al. (1993) observed no such a effect on pregnancy outcome. However, Norman et al. (1994) found a significant prolongation of pregnancy and a reduction in fetal morbidity when ampicillin and metronidazole were added to tocolysis and corticosteroids. These conflic­ ting results may reflect different genital tract colonisations and/or aetiologies of preterm labour. Further randomised trials are needed to asses the value of antibiotic supplement in standard tocolytic treatment. In the case of PPROM without active labour, administration of antibiotics seems to prolong the time interval to the onset of delivery, with a halving of the neonatal infection rate . No influence, however, was seen on the perinatal mortality rate (Crowleyb 1992). The optimal antibiotic or combination of antibiotics, together with the dose, duration of treat­ ment and route of administration is yet to be determined. In a small number of carefully selected cases, emergency cervical cerclage might prolong pregnancy and improve fetal outcome when women present with already far dila­ ted cervices and intact membranes (MacDougall and Siddle 1991).

SUMMARY

Although still incomplete, there is a growing understanding of the aetiology of preterm labour and delivery. Preterm birth is a multifactorial problem with different causes (Creasy 1991). Approximately one fourth of preterm births are induced because of complications of pregnancy in which a presumed threat to the well-being of mother and fetus indicates an early delivery (Goldenberg et al. 1990). In contrast with this, so called, medically indicated preterm birth stands preterm birth of unknown cause, also called spontaneous preterm birth, and preterm birth after prelabour rupture of membranes. Spontaneous preterm birth seems to be less "spontaneous" than its definition implies. Subclinical infection may play an important role in starting the preterm labour process, especially in prelabour rupture of membranes preterm (Minkhof et al. 1984). Prevention of preterm birth can be achieved by two approaches. First by activities aimed to prevent the initiating of preterm labour and second, by inhibition of the already started preterm labour process. Preventing the initiation of preterm labour necessitates the identification of patients at risk for developing preterm labour or preterm prelabour rupture of membranes. To date predictive screening tests, such as risk factor scoring, uterine activity monitoring and various biochemical tests, score poorly both in sensitivity and in positive predictive value (McLean et al. 1993). Identification of pregnant women with bacterial vaginosis and sub­ sequent antibiotic treatment seems promising in preventing the initiation of preterm labour (McCoy et al 1995). The well known risk factors associated with preterm labour and delivery are: young (<20 years) and advanced (<35 years) maternal age, a previous history of preterm birth or midtrimester pregnancy loss, genital tract infection, multiple gestation, uterine anomalies,

28 AETIOLOGY OF PRETERM LABOUR AS A BASIS FOR PREVEmiON social poverty, and heavy, long, standing work (Lumley 1993). Many predictive risk factors are related to past obstetric history or current pregnancy complication and are therefore not preventable. Changing socio-economic status and workload of pregnant women did reduce the incidence of preterm birth in France, but it can be questioned if this attitude is worthwhile in other countries. Inhibition of the already started preterm labour process can be obtained by tocoly­ tic drugs, but their effectiveness lasts only for a few days (Keirse et al. 1989). Appropriate drugs for use in preterm labour are betamimetics and inhibitors of prostaglandin synthe­ sis (indomethacin). These tocolytic drugs do not improve fetal outcome by themselves but only in combination with administration of corticosteroids and, if necessary, antepartum transport to centres with appropriate perinatal and neonatal facilities. Preterm labour is no longer seen as a normal labour process that started to early. Different labour inducing mechanism have been identified and apart from the recently recognized infectious aetiology other possible causes, such as immunologic processes and hormonal changes have received much attention (Challis and Mitchell 1994).

29 30 CHAPTER 3

TOCOLYSIS Chapter 3 TOCOLYSIS

INTRODUCTION

In the last decades a wide variety of drugs and other interventions have been used in attempts to suppress uterine contractions in threatening preterm birth, only a few of these are still used today, (table 1.) Despite this variety of agents we are still searching for an ideal tocolytic drug that prevents the initiation of labour and/or inhibits the process when it started preterm. In view of the multifactorial aetiology of preterm labour (Lettieri et al. 1993) such a drug is not likely to be found in the near future. In the meantime betamimetic agonists, magnesium sulphate and inhibitors of the pros­ taglandin synthesis are worldwide the most frequently used drugs to stop preterm uterine contractions and prevent preterm labour and birth. Of these only the betamimetic ritodrine- hydrochloride, is approved by the FDA for use in preterm labour in the U.S.A. (Anon. 1980). Promising results have been obtained with oxytocin antagonists, such as Atosiban (Melin 1993, Romero et al. 1994) and, to a lesser extent, with calcium channel blockers, such as Nifedipine (Ulmsten et al. 1980, Keirse et al. 1989, Besinger 1994). Recently, new favou­ rable results with Nifedipine are presented (Papatsonis et al. 1996). To date, clinical expe­ rience with these agents is still limited and an accurate assessment of there value; if any, is therefore, not yet possible.

DEFINITIONS

Tocolytic drug treatment is used to stop uterine contractions in preterm labour and /or to prevent the development or recurrence of preterm uterine contractions. Definitions to deli­ neate these treatment goals can be made as follows:

Active treatment: Initial treatment undertaken to stop uterine contractions in threatening premature labour.

Maintenance treatment: Ongoing treatment after successful active treatment with the aim to maintain uterine quiescence.

Prophylactic treatment: Medical intervention for the prevention of preterm delivery in patients thought to be at increased risk of preterm labour, but currently not in labour.

TOCOLYTIC DRUGS:

BETAMIMETIC AGENTS

In 1961 the first betamimetic tocolytic agent, isoxsuprine, was proposed for the treatment of preterm contractions (Bishop and Woutersz 1961). The clinical use of isoxsuprine was subse­ quently limited by its wide range of nonselective beta-adrenergic side effects. Over the next 15 years, a wide variety of selective betamimetic medications were proposed as tocolytic treat­ ment (see table 1; adapted from Keirse et al. 1989). Of these, ritodrine (Wesselius-De Casparis et al. 1971), fenoterol (Edelstem and Baillie 1972), terbutaline (Ingemarsson 1976) and sal- butamol (Liggins and Vaughan 1973), found their place in the treatment of preterm labour.

32 TOCOLYSIS

Table 1 Summary of approaches used to inhibit preterm labour in the past 40 years and their purported success rates in the first English language publication documenting their use.

No of Per cent Agent Year Authors women Criterion of success success

Relaxin 1955 Abramson and Reíd 5 delivery after 36 weeks 100

Isoxsupnne 1961 Bishop and Woutersz 120 contractions delayed 24 hours 82

Ethanol 1967 Fuchs et al 52 delivery delayed 72 hours 67

Огсіргепаіше 1970 Baillie et al 30 delivery after 36 weeks 70

Mesupnne 1971 Barden 17 delivery delayed 24 hours 53

Ritodrine 1971 Wesselius-De 43 not delivered during treatment 80 Caspans et al

Fenoterol 1972 Edelstein and Balille 28 delivery delayed 1 week 71

Salbu tamol 1973 Liggms and Vaughan 88 delivery delayed 24 hours 85

Indomethaon 1974 Zuckerman et al 50 arrest of contractions 80

Sulmdac 1992 Carian et al 18 delivery delayed >7 days 55

Naprosyne 1979 Wiqvist 10 decrease in contraction frequency 100

Sodium 1974 Gyory et al 50 diminished uterine activity 100 salicylate

Buphenine 1975 Castren et al 43 birthweight = 2,500 g 86

Terbutaline 1976 Ingemarsson 15 not delivered during treatment 80

Nifedipine 1977 Andersson 10 delivery delayed 3 days or more 100

Magnesium 1977 Steer and Petne 31 contractions stopped 24 hours 77 sulphate

Flufenanuc 1978 Schwartz et al 18 delivery delayed 24 hours 83 and

Dia70xide 1984 Adamsons and Wallach 118 complete cessation of contractions 94

Utrogestan 1986 Erny et al 57 decrease m contraction frequency 76

Oxytoan 1987 Akerlund 13 inhibition of contractions 100 analogue et al

Modified from Keirse 1989

33 Chapter 3

Mechanism of action

Like the endogenous catecholamines epinephrine (adrenalin) and nor-epinephrine (nor­ adrenaline) betamimetics stimulate beta-adrenergic receptors in the uterus and other organs. In utero this receptor-stimulation activates the adenyl cyclase system which leads to increased levels of intracellular cAMP (cyclic adenosine monophosphate). These, in turn, initiate a series of reactions resulting in reduced intracellular calcium levels and redu­ ced sensitivity of the myosin-actin contractile elements to the available calcium (Caritis et al. 1979, Roberts 1981). The final step preceding the reaction of the two proteins actin and myosin, which is responsible for the shortening of the muscle cell, is phosphorylation of the light chain of myosin (Word et al. 1993). This phosphorylation of myosin is controlled by the enzyme myosin light chain kinase (MLCK), the activity of which is directly related to the intracellular concentration of calcium. Prolonged exposure to betamimetic drugs leads to a decrease in response (tachyphylaxis) which is generally believed to be due to down-regulation of the receptor (Harden 1983, Berg et al. 1985, Caritis et al. 1987, Ekblad et al. 1987). Side effects can be explained by the same influence of betamimetics on cell activity in all other organs of the body (Eskes and Essed 1979).

Efficacy

An overview of controlled randomised trials performed with betamimetics shows a clear significant benefit in terms of prolongation of pregnancy for 24 and 48 hours and a tend­ ency to benefit prolongation beyond 37 weeks, whereas perinatal mortality and the fre­ quency of severe neonatal respiratory problems remain unchanged (table 2; Keirsec 1995). In the efficacy of active treatment there seems to be no difference between the beta­ mimetics used, but there is a very limited amount of unbiased data from which this can be judged adequately. Much of the efficacy and effectiveness results relates to ritodrine trails (13 of 17), the drug of choice in many Western European countries and the USA. The Canadian Multicentre Study (1992) led to much criticism about the assumed efficacy of ritodrine in preterm labour. The Canadian investigators randomised 708 women in pre­ term labour to receive intravenous ritodrine or placebo. Although they demonstrated a sig­ nificant reduction in the number of women delivering within 48 hours in the treatment arm (P<0.001), there was no influence on the incidence of low birthweight or perinatal mortality. A possible explanation can be the fact that the proportion of patients receiving glucocorticosteroids was low (35%) and not different between the treatment and the place­ bo groups although the ritodrine group has a significantly longer delay of delivery (ran­ domisation to delivery interval <7 days; ritodrine 38.2% versus placebo 47.2%, difference -9.0, 95% confidence interval -14.8 to -3.2). Also there was a high number of women with an advanced duration of pregnancy up to 35 weeks (32 - 35 weeks of gestation; ritodrine group 139 (39.5%), placebo group 144 (40.4%) from whom one would not expect improve­ ment in fetal outcome to result from postponing delivery. On the other hand there was a trend towards a lower mortality rate and a lower rate of very preterm births in the sub­ group of women with onset of preterm labour between 24 to 27 weeks. Especially in this group of extremely preterm pregnancies any prolongation, irrespective of how short it is, can add benefit in terms of perinatal outcome. It has been estimated that the rate of survi­ val increases by more than 1% to 3% per day between 25 and 27 weeks of gestation (Copper et al. 1993, Fanaroff et al. 1995).

34 TOCOLYSIS

Betamimetics stop contractions for at least 48 hours in a significant proportion of women and this time gained should be used to the best effect i.e.: for reassessment of fetal well-being, administration of glucocorticosteroids and in utero transfer to tertiary neona­ tal care centres.

Table 2 Betamimetic tocolytics in preterm labour. (17 trails reviewed)

ODDS 95 % CI Effect on ratio LO HI

Delivery < 24 hours 0.31 0.24-0.41 Delivery < 48 hours 0.54 0.43-0.69 Delivery before 37 weeks 0.83 0.66-1.02 Birth weight> 2500 grams 0.77 0.62-0.95 RDS or severe resp.probl 0.92 0.72-1.16 Death not due to lethal malformation 0.90 0.60-1.37

(Keirse' 1995)

Dosage schedules for betamimetics

Betamimetics have been administered by the oral, intravenous, intramuscular and subcu­ taneous routes depending, to some extent, on the type of drug used.

Active treatment

In active preterm labour, in general, an incremental intravenous dose schedule is applied that consists of a low-starting dose which is increased every 10-15 minutes until uterine quiescence is achieved and/or maternal or fetal side effects prohibit further increases in the dose (Barden et al. 1980). If the contractions disappear, the infusion rate is held un­ changed for 24-48 hours whereafter it is decreased and later on stopped if possible. Commonly employed dose schedules for betamimetics are listened in table 3.

Table 3 Classical dosage schedules for intravenous adminisstration of betamimetics in preterm labour.

Drug Initial dose Step-Up\time Maximum dose i.v. rate i.v. rate

Ritodrine 50-100 Rg/min 50μg\15min 350 μg/min Terbutaline 10-15 μg/min 5 μg\15min 25 μg/min Fenoterol 2 μg/min 0.5 μg\20min 4.0 μg/min Salbutamol 10 μg/πvin 5 μg\10min 40 μg/min

35 Chapter 3

Most clinical investigations have used an intravenous route for parenteral admini­ stration of ritodrine (t„, - 2-3 hours). Yet, some investigators believe that intramuscular administration (5-10 mg every 2-4 hours) produces superior results and has fewer side effects (Larsen et al. 1986, Schever et al. 1981). Other studies could not find a difference in short-term clinical outcome, but confirmed that side effects were less common with intra­ muscular administration (Larsen et al. 1980, Gonik et al. 1988). Terbutaline (tI/2 = 3.7 hour) is mostly given intravenously, although recently subcutaneous administration has been given much attention (Stubblefield and Heyl 1982, Lam et al. 1988). The common subcuta­ neous dose is 0.25 mg every 20-60 minutes until contractions subside. The ease of admini­ stration makes this route clinically attractive, but it does not preclude potential overdoses (Hill 1986, Perry et al. 1995). The route of administration of salbutamol (t1/2 = 6 hours) is intravenously or intramuscularly, while fenoterol (t1/2 = 20 min.) is given intravenously. With increasing understanding of the pharmacokinetic properties of these potent betamimetic drugs other dosage schedules have been proposed (Steenhoek 1982). Pulsatile administration of betamimetics prevents the myometrial desensitisation for the beta-adre­ nergic agonist because is does not reduce the beta-adrenergic receptor density nor adenyl- cyclase activity in contrast to continuous administration (Caritis et al. 1991, Ke et al. 1984, Levin et al. 1980, Berg et al. 1982, Casper and Leye 1986). These effects seem to be related both to the level of the betamimetic plasma concentration as to the total dose administered which is lower when given pulsatile (Caritis et al. 1991, Spätling et al. 1989). Much of this evidence is obtained by experimental data on myometrial strips or in animal studies. Spätling et al. (1989), in a non-randomized study however, used a pulsatile dose scheme for fenoterol in women with preterm labour and compared it with the traditional incre­ mental scheme. He found that intermittent administration of fenoterol required less beta­ mimetic agent for a comparable therapeutic success. There was no significancy in mater­ nal side effects with the intermittent schedule; no differences in fetal outcome were obser­ ved. The same was found for intermittent subcutaneously administered terbutaline (Stubblefield and Heyl 1982). In efforts to reduce the maximum and total dose of ritodrine needed for prolonged uterine quiescence in preterm labour Caritis et al. (1990) and Holleboom et al. (1987, 1993) proposed loading dose administration and rapid reduction of the ritodrine infusion rate after the contractions ceased. The theoretical gain in reduc­ tion of infusion rate and total dose of ritodrine used, could not be confirmed by a ran­ domised comparison of the loading and incremental dose models, but maternal side effects were significantly less when the loading dose model was used (Holleboom et al. 1996; see chapter 6).

Maintenance treatment

Continuation of betamimetic treatment after successful arrest of active preterm labour to prevent recurrences of uterine contractions is generally used although there are not many studies to support this treatment option. Four small controlled studies have investigated the efficacy of oral maintenance treatment with betamimetics (Creasy et al. 1980, Brown and Tejani 1981, Smit 1983, Ricci et al. 1990). Creasy' et al. (1980), Ricci et al. (1990) and Smit (1983) used one or two tablets 10 mg ritodrine every 3-4 hours and Brown and Tejani (1981) 2.5 mg terbutaline tablets every 3-4 hours. Despite the small sample size of patients groups (total of less than 275 patients) and the heterogeneity of initial treatment (ritodrine intra­ venously or intramuscularly, magnesium sulphate intravenously and ethanol intrave­ nously), these studies indicate that oral betamimetics are able to reduce the incidence of

36 TOCOLYSIS recurrent preterm labour (Keirsed 1995). However there was no reduction in the incidence of preterm delivery, nor a decrease in perinatal morbidity/mortality and respiratory dis­ tress syndrome. The lower incidence of recurrent preterm labour may, however, be a bene­ ficial outcome in itself, when considered in terms of costs of re-admission and hospitalisa­ tion of patients with recurrent preterm labour. To overcome the inconvenience of frequent drug intake (every 3-4 hours day and night) a sustained release administration form of ritodrine was introduced which reduces the drug-intake to three times daily (Essed 1987). High and stable ritodrine plasma levels could be obtained, without serious maternal side effects, with two capsules of 40 mg rito­ drine sustained release three times daily comparable with those during a continuous intra­ venous infusion rate of 50 μg/min ritodrine (Essed et al. 1987, Witter et al. 1988). Whether this sustained release medication form results in better efficacy in prolonging pregnancy remains to be established though (see chapter 7). Interesting results were obtained with subcutaneous administration of terbutaline and salbutamol via a portable infusion pump (Lam et al. 1988, Milliez et al. 1992). Milliez et al. (1992) found no difference in the frequency of preterm birth between oral salbutamol and continuous subcutaneous administration of salbutamol, but a significant decrease in recurrent preterm labour. Lam et al. (1988) started subcutaneous intermitted terbutaline in 9 patients who had failed to respond to oral terbutaline treatment after initial magnesium sulphate treatment. Only one patient delivered preterm and this was at 32 weeks of gesta­ tion after 7 weeks of pump use. The daily dose of terbutaline required was very low (less than 3mg/day) which was explained by less receptor down-regulation with the pulsatile dosage scheme. The sample size of the study, however, is far to small to draw any conclu­ sion on efficacy!

Side effects of betamimetics

In 1925 Rucker found that small amounts of adrenaline give a temporary relaxation of ute­ rine contractility. This observation was confirmed by Bourne and Brun (1927) with intra­ venous administration of adrenaline during labour. Dose dependent relaxation or contrac­ tions were observed by administration of cathecholamines a phenomenon that could be explained by the hypothesis of Ahlquist (Ahlquist 1948). He introduced two kind of adre­ nergic receptors: alpha- and beta-adrenergic receptors. Alpha-receptor stimulation causes contraction, whereas beta-receptor stimulation gives myometrial relaxation. Other alpha- receptor effects are predominantly vasoconstriction while beta-receptor stimulation causes vasodilatation and increase in heart frequency. These alpha- and beta-receptors are not utero specific and are found in all organs throughout the body. Two types of beta-adrenergic receptors (Lands et al. 1967) have been postulated in humans: Beta, receptors predominate in the heart, small intestine and adipose tissue; beta2 receptors are more prevalent in smooth muscle fibres of the uterus, blood vessels, bron­ chioles and diaphragm. With growing knowledge of the two types of adrenergic receptors (alpha and beta receptors) and two types of beta-adrenergic receptors (beta! and beta2 receptors) with their different effects, efforts were made to synthesize adrenaline compounds with a more spe­ cific beta2 action; the so called selective betamimetic agents. Nevertheless, even the most selective betamimetic agents activate both beta, and beta2 receptors and, therefore, produ­ ce diffuse multi-organ effects. The majority of undesirable side effects of betamimetics, stems from their non-selec-

37 Chapter 3 rive pharmacological action on other, extra-uterine, organ systems. Common undesirable side effects seen with "so called" selective betamimetic tocolytic agents include significant tachycardia, increase in stroke volume, cardiac arrhythmia, lipolysis and glucose derange­ ments as part of this generalised stimulation of the beta-adrenergic system (Eskes and Essed 1979).

Maternal side effects/complications

The most frequently observed maternal symptoms are nausea, vomiting, tremor and pal­ pitations. Women can also experience headache, thirst, restlessness, nervousness and chestpain (Keirse et al. 1989, Grospietsch and Kuhn 1984).

Cardiovascular. The most common effects on the cardiovascular system are increase in heart rate, systolic blood pressure, stroke volume and cardiac output due to a generalised vaso­ dilatation (Wagner et al. 1981). Cardiac output can increase up to 60% over baseline levels (Bieniarz et al. 1974). As a result of increase in systolic and decrease in diastolic blood pres­ sure, mean arterial pressure does not change significantly (Bremme et al. 1986). Cardiac arrhythmias have been reported, most commonly supraventricular tachycardia. (Schneider et al. 1988, Kjer and Pedersen 1982). Other arrhythmias include atrial fibrilla­ tion, premature atrial contractions and ventricular ectopy (Chen and Lew 1979, Fredericksen et al. 1983). Increased heart rate and myocardial contractility can predispose to myocardial ischemia because of the decreased coronary artery perfusion due to de­ creased diastolic bloodpressure and diastolic filling time (Michalak et al. 1983). Whether ECG alterations, during tocolysis, represent myocardial damage or are just a physiological adaption to the new situation remains unclear (Hendricks et al. 1986, Mulders et al. 1987). In all probability, the ECG criteria for discontinuation of beta- mimetic tocolysis need to be reassessed (Besinger 1994).

Pulmonary oedema. In literature, the incidence of pulmonary oedema, one of the most life threatening complications of betamimetic treatment, varies from 0.01% to 9% of patients treated with these tocolytics, but more realistic is an incidence of 0.25% or less (Besinger 1994). More than 95 cases of pulmonary oedema have been reported in the literature (Hankins 1991). The cause of pulmonary oedema appears to be multifactorial. Many cases are secondary effects of fluid overload resulting from aggressive intravenous hydration, prior to tocolytic treatment, to prevent diastolic hypotension and from the antidiuretic effect of high doses of betamimetics itself (Keirse et al. 1989, Pisani and Rosenow 1989). Other predisposing risk factors are: twin pregnancy, preexisting cardiac disease, hyperten­ sion, anaemia, renal disease, need for transfusion, underlying maternal infection, prolong­ ed intravenous tocolysis and multi-drug therapy (Besinger 1994, Pisani and Rosenow 1989). Careful control of fluid in- and output, administration of tocolytics by an infusion pump, adequate patient selection, alert reaction on early signs of pulmonary congestion are therefore recommended to prevent pulmonary oedema.

Metabolic. All betamimetics influence carbohydrate metabolism and increase maternal blood glucose about 40% with a concurrent increase in insulin and glucagon secretion (Eskes and Essed 1979, Spellacy et al. 1978, Grospietsch and Kuhn 1984). This promotes gluconeogenesis and gluconeolysis. Insulin levels rise as a response to increased glucose concentration and also as a result of direct stimulation of beta-adrenergic receptors in the

38 TOCOLYSIS maternal pancreas (Caldwell et al. 1987). These effects are also more marked when beta- mimetics are given together with glucocorticoids, which also have diabetogenic effects. These effects are more pronounced in diabetic women and it increases their insulin require­ ments (Lenz et al. 1979, Wagner et al. 1982). Together with induction of lipolysis, by beta- mimetics, leading to an accumulation of acidic metabolites, this can cause severe ketoaci­ dosis (Thomas et al. 1977, Schilthuis and Aarnoudse 1980). This tendency to keto-acidosis has been reported to be present also, but to a lesser degree, in gestational diabetes (Richards and Klinkenberger 1987). Serum potassium concentrations decrease rapidly at initiation of treatment with betamimetics (Grospitsch and Kuhn 1984). This decrease is probably due to a net flux of potassium from the extracelluar to the intracellular space and it is transient. Potassium replacement therapy is not indicated and levels normalize within 24 hours (Peters et al. 1984).

Other risks. Other significant maternal effects described with the use of betamimetics inclu­ de transient elevations of maternal serum transaminase, paralytic ileus, drug-induced vas­ culitis, agranulocytosis and toxic skin reactions.(Suzuki et al. 1985, Nair et al. 1976, Wang- Cheng and Davidson 1986, Muro et al. 1991, Bosnyak et al. 1991). Exacerbation of pre-exis­ ting neuromuscular disease has been described in a patient with myasthenia gravis lead­ ing to respiratory arrest (Catanzarite et al. 1984) and cerebral vasospasm in patients with a history of migraine (Rosene et al. 1982).

Fetal side effects/complications

Betamimetics rapidly cross the placenta and this transfer induces a stimulated beta-adre­ nergic state in the fetus (van Lierde and Thomas 1982, Gandar et al. 1980, Gross et al. 1985) This evokes roughly the same effects as it does in the mother. Fetal tachycardia is the most directly observed effect after initiation of treatment (Caritis et al. 1977, Shenker 1965). No pathologic fetal arrhythmias have been observed in short term fetal electrocardiograms (Shenker 1965). However, neonatal supraventricular tachycardia has been described after prolonged maternal ritodrine administration (Hermansen and Johnson 1984) as have other fetal tachy-arrhythmias (Brosset et al. 1982). Since the metabolic effects of betamimetics cause hyperinsulism and hypoglycaemia in mother and fetus after birth, careful assessment of blood glucose levels is essential in infants born during or shortly after tocolysis (Essed 1983, Epstein et al. 1979). Recently, an association between betamimetic tocolysis and intraventricular haemor- hage (IVH) has been reported (Groóme et al. 1992, Pranikoff et al. 1991). Others have fail­ ed to demonstrate an increased rate of IVH in similar conditions (Laros et al. 1991). Long-term follow-up studies of infant and child development after exposure to betamimetics in utero showed no difference between these children and unexposed con­ trols (Hadders-Algra et al. 1986, Polowczyk et al. 1984).

Conclusion

A major benefit from tocolytic treatment with betamimetics can be derived from a prolon­ gation of pregnancy, even if short, particularly at gestational ages of less than 32 weeks (Goldenberg et al. 1984). The time gained can and should be used for the administration of corticosteroids to accelerate fetal (lung) maturation (Crowley et al. 1990, Crowley3 1995),

39 Chapter 3 reassessment of fetal well-being and, if necessary, antepartum transport to a centre with appropriate facilities for perinatal and neonatal care. After 34 weeks of gestation prolon­ gation of pregnancy has little effect, if any, on fetal outcome and the potential side effects and risks of tocolytic treatment with betamimetics probably overweigh their benefits.

INHIBITORS OF PROSTAGLANDIN SYNTHESIS

Prostaglandins play a major role in the initiation of labour. Therefore suppression of the production of endogenous prostaglandin synthesis is a logical approach in the treatment of preterm labour (Keirse 1985,1992). In a retrospective study, Lewis and Schulman (1973) showed prolongation of preg­ nancy in chronic aspirin users. In the same year Waltman et al. (1973) published an exten­ sion of induction-abortion interval, in women undergoing 2nd-trimester abortion by hypertonic saline, caused by inhibitors of prostaglandin synthesis. This was followed by the first published report, in 1974, on the application of indomethacin in the treatment of preterm labour (Zuckerman et al. 1974). Several agents with widely different chemical structures and pharmacokinetic pro­ perties inhibit prostaglandin synthesis (Keirse 1981). They include acetylsalicylic acid (aspirin), indomethacin, naproxen, sulindac and several fenamates (like fenoprofen). Indomethacin is the most widely used inhibitor of prostaglandin synthesis for the treat­ ment of preterm labour. Often these agents are referred to as prostaglandin synthetase inhibitors. However, since there is no such enzyme as prostaglandin synthetase, these drugs are more appro­ priately referred to as inhibitors of prostaglandin synthesis (Keirse et al. 1989).

Mechanism of action

Prostaglandins are important mediators of uterine activity by activating the calcium chan­ nels within the myometrial cell membrane, as well as functioning as secondary messengers to modulate calcium release from the sarcoplasmatic reticulum (Carsten and Miller 1987). All of the currently available inhibitors of the prostaglandin synthesis act on the cyclooxy- genase prostaglandin endoperoxide synthase enzyme. It is present in high concentrations in the myometrium of the pregnant uterus, but is found throughout the body in both women and men (Moonen et al. 1984). Due to their site of action in the arachidonic casca­ de not only prostaglandin synthesis is inhibited by these agents but also the production of prosta-cyclin and tromboxaan A2. Aspirin causes irreversible inhibition of the enzyme cyclo-oxygenase by acetylation whereas indomethacin acts by competition with arachidonic acid for this enzyme. When indomethacin levels decrease, enzyme activity resumes.

Efficacy

The largest clinical experience with indomethacin as first-line tocolytic agent involved 252 patients and 88 percent of patients were reported to have a prolongation for more than one week (Zuckerman et al. 1984). Keirse (Keirse* 1995) combined several clinical trails in a meta-analysis and concluded that indomethacin in comparison with placebo was more effective in delaying delivery for 48 hours, for 7-10 days and in preventing delivery before 37 weeks and reducing the incidence of low birth weight. There was a tendency toward

40 TOCOLYSIS reduction of fetal and neonatal death, but this was not significant. The incidence of respi­ ratory distress syndrome was not altered by the use of indomethacin.(table 4) Overall the tocolytic effect of indomethacin was shown to be equally effective or even superior to betamimetics using data derived from randomised controlled trials (Morales et al. 1989, Kurki et al. 1991). Sulindac, a inhibitor of prostaglandin synthesis closely related to indomethacin in structure and mechanism (Nuki 1983), has been shown to be as effective as indomethacin with less fetal side effects (Carian et al. 1992). It is a prodrug that becomes active only after conversion to a sulphone metabolite in the liver. Probably the fetal liver is to immature to synthesize active metabolites of Sulindac, which explains the low incidence of fetal side effects. Sulindac seems promising in the treatment of active labour and for maintenance (Carian et al. 1995). This will need to be confirmed, though, in appropriately controlled clinical research.

Table 4 Effect of indomethacin in preterm labour.

ODDS 95 % CI Effect on ratio LO HI

Delivery < 48 hours 0.14 0.06 0.34 Delivery < 7-10 days 0.39 0.24 0.62 Delivery < 37 weeks 0.43 0.28 0.65 Birth weight < 2500 gr 0.51 0.35 0.72 Fetal and neonatal death 0.61 0.33 1.11 Respiratory distress 0.63 0.25 1.59

(Keirse11995)

Dosage scheme

Indomethacin can be given orally and as rectal suppositories. Tablets of 25 mg and 50 mg and suppositories of 50 mg and 100 mg are available. Usually, a starting dose of 100 mg rectally or 50 mg orally followed by 25 mg orally every 4 hours for 24-48 hours is recom­ mended (Morales et al. 1989, Niebyl et al. 1980). Sulindac is administered orally at a dose of 200 mg every 12 hours for 48 hours.

Maternal side effects/complications

In contrast to aspirin, the effect of indomethacin upon maternal platelet function is rever­ sible, because of the competitive binding of cyclo-oxynase, and there are no reports of excessive maternal haemorrhage during preterm parturition (Besinger 1994). Neverthe­ less, the effect on platelet function and bleeding time cannot be ignored. Gastrointestinal irritation and proctitis are common side effects, but in general they are tolerated well by patients without a history of peptic ulceration (Zuckerman et al. 1984, Morales et al. 1989). Because of their anti-inflammatory and anti-pyretic effects, inhibitors of prostaglandin synthesis could theoretically mask occult chorioamnionitis but it is not known whether this is a real concern in clinical practice.

41 Chapter 3

Fetal side effects/complications

Prostaglandin synthesis inhibitors cross the placenta and may influence several fetal func­ tions (Traeger et al. 1973, Wilkinson 1980). Most important and consistent are the influences on the cardio-pulmonary circulation, the renal function and haemostasis (Keirse 1981).

Cardiopulmonary risks. There is extensive evidence that inhibitors of the prostaglandin syn­ thesis can cause constriction and closing of the ductus arteriosus leading to persistent fetal circulation (Keirse 1992). The risk of this complication increases with fetal exposure for lon­ ger than 48 hours and increases dramatically in pregnancies of more than 32 weeks gesta­ tion (Moise 1993). The incidence of indomethacin-induced persistent pulmonary hyper­ tension, a life threatening event, is estimated to be 5% (Besinger 1994). A higher incidence of patent ductus arteriosus in indomethacin-exposed infants has been observed (Besinger et al. 1994, Norton et al. 1993). More indomethacin-exposed infants with a patent ductus arteriosus required surgical ligation because of either a lack of initial response or a reopening of the duct after postnatal indomethacin therapy (Norton 1993).

Renal side effects. Severe oligohydramnios has been reported during use of indomethacin in preterm labour (Itzkovitz et al. 1980, de Wit et al. 1988, Goldenberg et al. 1989). The inci­ dence of this complication has been reported to vary between 10 % (Morales et al. 1989) and 30 % (Bivins et al. 1993). Probably an alternation in prostaglandin-mediated tubular function is responsible for this event. It appears to be dose dependent and reversible upon discontinuation of indomethacin administration (Goldenberg et al. 1989), although some rapports show subsequent renal failure in the newborn (Veersema et al. 1983, Itzkovitz et al. 1980, Norton et al. 1993).

Haemostasis. Prostaglandin synthesis inhibitors all act on platelet function and inhibit pla­ telet aggregation causing a prolonged bleeding time. Especially aspirin is a strong inhibi­ tor of platelet function by its definitive acetylation of the cyclooxygenase enzyme making it permanently nonfunctional.

Other effects. An association between indomethacin and intraventricular haemorrhage has been raised and a higher incidence of necrotising enterocolitis is reported after its use (Norton et al. 1993).

Conclusions

In summary, inhibitors of prostaglandin synthesis are powerful, effective and easily admi­ nistered tocolytic agents for the treatment of preterm labour. Their severe potential fetal side effects limit their use. The use of prostaglandin synthesis inhibitors should be restrict­ ed to short periods of less than 48 hours and before the 32* week of gestation.

MAGNESIUM SULPHATE

The first report on the inhibitory effect of magnesium sulphate on the myometrium dates from 1959 (Hall et al. 1959).

42 TOCOLYSIS

Mechanism of action

Its mechanism of action is still unknown, but it is almost certain that magnesium acts by substituting for calcium at the level of the myometrial cell (Carsten and Miller 1987). Mag­ nesium activates adenyl cyclase and increases cAMP, thus reducing intracellular calcium.

Efficacy

Controlled studies evaluating the efficacy of magnesium sulphate in inhibiting preterm labour are scarce. Some comparative clinical trials on magnesium sulphate and betamime- tics have demonstrated equivalent clinical effectiveness in delaying preterm delivery for 24-72 hours (Tchilinguirian et al. 1984, Hollander et al. 1987) with less maternal side effects, but others could not find such a beneficial effect of magnesium sulphate in the treatment of preterm labour (Cox et al. 1990). A meta-analysis of these above mentioned results did not show any beneficial effect of magnesium sulphate on postponing preterm delivery, on the incidence of preterm delivery nor on any improvement of fetal outcome (Keirse'81995).

Dosage scheme

Active treatment. Magnesium sulphate is given intravenously in a loading dose of 4-6 grams during 20-30 minutes followed by administration of 2-4 grams every hour. Serum concentra­ tions of 4 to 8 mEq/L appear to be necessary for reduction of myometrial activity (Elliott 1985). Maintenance. There are no data to support the use of oral magnesium sulphate in mainte­ nance therapy. (Keirse 1995h)

Maternal side effects/complications

Magnesium sulphate causes vasodilatation, through its action on vascular smooth muscle, and this may lead to hypotension, hot flushes, palpitations, headache, nausea and vomi­ ting. More serious side effects are related to overdose. Magnesium serum concentrations of 4-8 mEq/L lead to a loss of deep tendon reflexes and concentrations between 12-15 mEq/L are accompanied by severe hypotension, respiratory depression and ECG changes. Cardiac arrest may occur above 15 mEq/L of magnesium sulphate (Pétrie 1981). Attention should be given to the maternal renal function. Magnesium sulphate is exclusively excreted in the urine and even a slight impairment of renal function may lead to unexpected overdose. Vital signs, urine output and deep tendon reflexes, besides magnesium serum con­ centrations, must be closely followed during treatment with magnesium sulphate in order to detect early signs of overdose and to prevent lethal complications.

Fetal side effects/risks

Magnesium sulphate rapidly crosses the placenta and fetal magnesium plasma concentra­ tions are the same as in the mother (Lipsitz 1971). Neonatal hypotonia and drowsiness have been reported in newborns born during or shortly after magnesium treatment (Pétrie 1981). Neonatal elimination of elevated magnesium levels may take 3 to 4 days. Alterations in neonatal calcium levels and unexplained bone déminéralisation after prolonged expos­ ure to magnesium sulphate have been reported (Holcomb et al. 1991, Lamm et al. 1988).

43 Chapter 3

Conclusion

Although magnesium sulphate inhibits uterine contractions, safe doses of magnesium sulphate are ineffective in preventing preterm birth. Higher doses may have potentially lethal side effects. This latter, together with the fact that its efficacy is not beyond doubt, prohibits further recommendation of this drug in the treatment of preterm labour.

CALCIUM ANTAGONISTS

Calcium antagonists also known as calcium channel blockers or calcium entry blockers include a wide range of different, and apparently unrelated compounds such as diltiaze- me, fendiline, nicardipine, nifedipine, nitrendipine, perhexiline, prenylamine, terodiline and verapamil (Andersson 1977). Some of these drugs (verapamil and nifedipine) have been used for the treatment of ischaemic heart disease, arterial hypertension and even for hypertension in pregnancy. The first report of the use of one of these agents, verapamil, in preventing preterm labour dates from 1972 (Mosler and Roosenboom 1972). Because of severe cardiovascular complications, impairment of atrioventricular conduction, dosage was limited and this study revealed no effects. Nifedipine, with less effects on atrioventri­ cular conduction velocity, has been tested since then as the calcium antagonist of choice in the treatment of preterm labour (Andersson 1977, Ulmsten et al. 1980).

Mechanism of action

The inhibition of uterine contraction is apparently due to a blockage of the voltage-depen­ dent calcium channels in the myometrial cell membrane, inhibiting calcium flux from the extracelluar space into the cell (Braunwald 1982, Carsten and Miller 1987).

Efficacy

The first published clinical studies showed enthusiasm about the efficacy of nifedipine in prolonging pregnancy and the lower grade of maternal side effects with this tocolytic agent (Ulmsten 1980, Read and Wellby 1986, Ferguson et al. 1990). A meta-analysis of con­ trolled trials (Keirse 1995') comparing betamimetics with nifedipine found no valid justifi­ cations for this enthusiasm. Newer studies seem encouraging (Janky et al. 1990, Glock and Morales 1993, Smith and Woodland 1993) and suggest efficacy rates comparable to those of betamimetics: i.e. effective in prolonging pregnancy with 24-48 hours (Kupfermine et al. 1993). The results of a recently published randomized trial, comparing ritodrine with nifedipine, are promising and show significantly less maternal side effects and better effectivity in postponing deli­ very in the nifedipine arm (Papatsonis et al. 1996).

Dosage scheme

Active treatment. Nifedipine is given orally (sometimes sublingually) in capsules. The oral starting dose is 30 mg (if necessary repeated after 30 min.) followed by 20 mg every 4-6 hours. Sublingual (broken capsule), the starting dose is 10 mg with every 20 minutes an­ other 10mg and a maximum of 40 mg in the first hour (Schneider 1994). Maintenance. 10 mg nifedipine every 8 hours per os.

44 TOCOLYSIS

Maternal side effects/complications

Major maternal complaints with nifedipine treatment include: tachycardia, headache and cutaneous flushing due to a decrease in mean arterial blood pressure. These side effects are generally similar to but less pronounced than with the betamimetic ritodrine (Ferguson et al. 1989). Advise to counteract the hypotension by intravenous fluid administration (Glock and Morales 1993) may predispose to pulmonary oedema (Ferguson et al. 1989). Slower atrioventricular conduction in the heart has also been observed. In routine use the above mentioned side effects appear to be minimal.

Fetal side effects/risks

There are some data concerning decreased uteroplacental circulation during nifedipine treatment (Calvin et al. 1983) due to the powerful vasodilatation and loss of autoregulation in human placental vessels (Maigards et al. 1984). However, doppler evaluation of utero­ placental circulations demonstrated minimal alteration in flow-velocity waveforms (Mari et al. 1989). Clinical experience about fetal and neonatal risks are limited and poorly docu­ mented, but tachycardia and septal hypertrophy have been reported (Childress and Katz 1994).

Conclusion

Given the limited clinical experience, to date, with this new class of tocolytics, calcium antagonists should not be used in routine clinical practice. Accurate assessment of their value and of their risk-benefit, including side effects, in randomised trails is still required before recommendations can be made.

OXYTOCIN ANTAGONISTS

There is increasing evidence for the role of oxytocin in the onset of term and preterm labour (Fuchs et al. 1982, Fuchs and Fuchs 1984, Fuchs et al. 1991). The number of myo- metrial oxytocin receptors increases rapidly towards the end of pregnancy and peaks during early labour. In preterm labour the amount of uterine oxytocin receptors is higher than in term pregnancy before labour, reflecting the sensitivity of the uterus for oxytocin (Fuchs and Fuchs 1984). Oxytocin acts directly on the myometrial muscle cell by receptor activation. Indirectly it acts on the myometrium by its role in decidual prostaglandin pro­ duction and possibly also in the fetal membranes (Fuchs' et al. 1982, Benedetto et al. 1990). Recent reports indicate a paracrine role for oxytocin within intrauterine tissues where oxy­ tocin gene expression has been found in fetal membranes and placenta (Lefebvre et al. 1992, Chibbar et al. 1993). In view of this, the search for oxytocin antagonists that can be applied to the treatment of preterm labour is not surprising. Since the early sixties several oxytocin analogues and antagonists have been developed and tested (Melin 1994). This has resulted in the development of [l-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn]-Oxytocin, better known as the oxytocin antagonist, Atosiban (Àkerlund et al. 1985). The first clinical report on the effectiveness of Atosiban in preterm labour was published in 1987 dealing with 13 women in preterm labour who had been treated with Atosiban (Àkerlund et al. 1987). All patients received Atosiban intravenously for 1 to 10 hours. Eighty-four per cent (11/13) of the patients met the criteria for successful tocolysis (defined as a decrease in the contrac­ tion frequency to less than 2 contractions per 20 minutes). Seven patients required tocolysis

45 Chapter 3 with ritodrine after discontinuation of Atosiban treatment. The overall rate of preterm de­ livery was 23% (3/13).

Mechanism of action

Oxytocin antagonists act by competing with oxytocin for its receptors on the myometrial cell membrane. They may also bind to receptors present in the decidua and fetal membra­ nes (Melin 1994). This has a double action on the level of intracellular calcium by: 1) pre­ venting release of calcium from the endosarcoplasmatic reticulum via direct cell membra­ ne receptor stimulation by oxytocin, and 2) preventing oxytocin-mediated release of prostaglandins from decidua and fetal membranes which in turn elevates the intracellular calcium concentrations. Decreased intracellular free calcium inhibits muscle contractility (see chapter Tocolysis; betamimetic agents: mechanism of action).

Efficacy

To date not enough clinical data are available to asses the efficacy of oxytocin antagonists, although the results with Atosiban are encouraging (Âkerlund et al. 1987, Anderson et al. 1989, Goodwin et al. 1994).

Dosage scheme

Atosiban is given intravenously by an infusion pump. The starting dose is 300 μg/min intravenously continuously for 2-8 hours until contractions disappear (Goodwin et al. 1994, Anderson et al. 1989). Also incremental dosage schemes have been used starting with 10-25 μg/min Atosiban increasing up to 100 μg/min (Âkerlund et al. 1987).

Side effects and complications

Oxytocin receptors are mainly found in the uterus. Therefore, in contrast with other toco­ lytics, oxytocin antagonists are presumed to have a greater uterospecificity. Indeed, the side effects of Atosiban when used in the treatment of preterm labour affeer to be of minor impor­ tance. Nausea, vomiting, headache and chestpain have been reported (Romero et al. 1994). Atosiban crosses the placenta (Valenzuela et al. 1993), thus exposes the fetus to some extent to the drug. Oxytocin may play a role in the development of cognitive functions, so careful follow-up of infants born after Atosiban treatment is mandatory! For maintenance treatment new oral oxytocin antagonists are in development (Evans et al. 1992).

Conclusion

Oxytocin antagonists are promising future tocolytic agents with a great uterospecificity and probably a low rate of side effects. Further studies are necessary to asses the value of these drugs.

OTHER TOCOLYTIC AGENTS

Progesterone

Progesterone is a classical inhibitor of uterine smooth muscle. Yet, the available evidence

46 TOCOLYSIS on its effect in active preterm labour when given intramuscularly (progesterone in oil) (Fuchs and Stakemann 1960) or orally (Utrogestan) (Erny et al. 1986), does not support nor suggest that it is effective in the inhibition of uterine contractions in preterm labour in vivo (Keirse et al. 1989). Progesterone should not be used any more in the treatment of preterm labour.

Ethanol

Ethanol (Fuchs 1965), while still albeit rarely used in clinical practice, has lost its applica­ bility because of serious side effects on mother and fetus. The efficacy of ethanol in the treatment of preterm labour is less than that of other tocolytics and its hazards far out­ weigh its potential benefits (Keirse et al. 1989). Therefore, ethanol should not be used any more in the treatment of preterm labour.

Diazoxide

Diazoxide (Landesman et al. 1969), a potent antihypertensive drug, mediates the adenyl- cyclase system in a manner similar to that of the betamimetics. Side effects and complica­ tions relate especially to the cardiovascular system and carbohydrate metabolism. No con­ trolled studies are available to assess its efficacy and safety in the treatment of preterm labour and, therefore, the drug should not be used (Keirse et al. 1989).

Anaesthetics

Aether and fluothane are anaesthetics with only historical importance in terms of treat­ ment of preterm labour (van Lierde et al. 1964).

OTHER PHARMACOLOGICAL APPROACHES

Antibiotic treatment

Preterm labour can be provoked by subclinical intrauterine infection with or without rup­ tured membranes (Romero and Mazor 1988, Romero et al. 1989, Gibbs et al. 1992, Lettieri et al. 1993). The efficacy of adjunctive antibiotics in the treatment of preterm labour has recently been reviewed (Kirschbaum 1993). There is no evidence that antibiotics adjuncti­ ve to tocolytic treatment in spontaneous preterm labour of unknown cause have a signifi­ cant beneficial effect on fetal outcome. On prolongation of pregnancy the results are con­ flicting (Crowley1 1995, Norman et al. 1994). In case of ruptured membranes antibiotics might prolong the interval to the start of the contractions (latent phase) and reduce the incidence of maternal and neonatal infection, but they have no demonstrable effect on peri­ natal mortality rate (Crowley 1995b). Given these results there is no reason for routine administration of antibiotics in pre­ term labour. In prelabour rupture of membranes preterm antibiotic treatment is likely to be appropriate when pursuing conservative management. The dose, optimal route of administration, type of antibiotic or combination of antibiotics has yet to be determined. Several controlled trials to address these questions are currently in progress.

47 Chapter 3

New developments

Many reports indicate that there is a relationship between intrauterine infection and the onset of preterm labour (Lettieri et al. 1993, Romero et al. 1989). Probably this is mediated by direct bacterial endotoxin production (such as lipase and proteolytic enzymes), but the host immune response, especially the production of cytokines by leucocytes and macro­ phages, may play an important role also (Mitchell et al. 1993). The interactions of the diffe­ rent cytokines such as tumour necrosing factor (TNF), interleukin 1 (IL-1), interleukin 6 (IL-6) and interleukin 8 (IL-8) on the arachidonic metabolism and thus on prostaglandin production supports this idea. New experimental tocolytic agents, such as 11-1 antagonists and urinary trypsin inhibitor, are in development (Romero and Tartakovsky 1992, Kanayama et al. 1995).

PROPHYLACTIC TREATMENT

For the prevention of preterm labour in women thought to be at risk to deliver preterm, progesterone, betamimetics and antibiotics have been investigated in controlled studies.

Progesterone

17-a-hydroxy progesterone caproate is administered by weekly intramuscular injections. Several small trials have been reported the last decades and a formal meta-analysis (Keirse et al. 1989, Keirse 1990) of the results of these trials showed a significant reduction in the incidence of preterm labour (Odds ratio 0.42, 95% CI 0.20-0.88), preterm delivery (Odds ratio 0.5,95% CI 0.3-0.85) and low birth weight (Odds ratio 0.46, 95% CI 0.27-0.80). There was no evidence for reduction in fetal morbidity and mortality. Only two studies reported on the effect on the incidence of preterm labour, and their results were conflicting (Hauth et al. 1983, Yemeni et al. 1985). Nowadays progesterone is not widely used (except in France) as a prophylactic treatment.

Betamimetics

All the studies done to date show that prophylactic use of betamimetics does not decrease the incidence of preterm birth nor of low birthweight (Keirse et al. 1989).

Antibiotics

The three studies reported about prophylactic antibiotic treatment in women considered to be at increased risk of preterm labour on the basis of genito-urinary culture findings or social circumstances did not reveal any evidence that this treatment reduces the incidence of preterm labour (Kirschbaum 1993). On the other hand Smaill (1995) found in a meta­ analysis that the antibiotic treatment of pregnant women with asymptomatic bacteriuria significantly reduces the incidence of preterm delivery and low birthweight.

GENERAL COMMENT

Their is extensive clinical evidence that betamimetics and inhibitors of prostaglandin syn-

48 TOCOLYSIS thesis are potent drugs for the inhibition of preterm labour (Keirse et al. 1989). Although the rate of prematurity has not declined the last decades despite the use of several tocolytic treatments, there is a beneficial effect of postponing preterm labour. Any time gain in itself, even if just a few days, increases, especially in extremely preterm labour, the infant survi­ val rate (Copper et al. 1993, Fanaroff et al. 1995). Administration of corticosteroids (Crowley31995), reassessment of fetal well-being and antepartal transport to an approp­ riate perinatal/ neonatal health centre (Lamont et al. 1983, Verloove - van Horick et al 1988) have proven their beneficial effect on fetal outcome and these activities can and must be arranged in the time gained by tocolytic treatment. The boundary of fetal viability for paediatric care has declined the last decades and stands around 24 weeks of gestation (Hack et al. 1991, Copper et al. 1993, Fanaroff et al. 1995, Rutter 1995). This decline in viability age has attributed to the rate of preterm birth by 1) better registration of the extremely preterm infants and 2) the possibility of patients attendants to induce preterm birth because of maternal/fetal pathology at an earlier gesta­ tional age. After 34 weeks of gestation there is hardly any gain in neonatal morbidity and mortality rate by postponing preterm delivery (Villar et al. 1994) and the possible hazards of side effects and complications of tocolytic treatment overweigh their possible benefits. Nowadays, in the treatment of preterm labour, we should focus our attention to 24 to 34 weeks of gestation. It is unrealistic, with the currently available tocolytic agents, to expect a decrease in the incidence of preterm labour/birth but we may expect a beneficial effect on fetal outcome by an appropriate use of these drugs. New drugs and drug treatment strategies are in the pipeline, such as, oxytocin anta­ gonists, calcium channel blockers, selective prostaglandin synthesis inhibitors with less side effects on the fetus and agents that act on cytokine production. Unless the promising first results obtained with these new drugs it is questionable if with these latter drugs the incidence of preterm birth will decline. A third of all preterm births is due to fetal or maternal pathology and another third presents with to far advanced preterm labour to stop the active labour process (Savitz et al. 1991, Meis et al. 1995, Villar et al. 1994). This leaves just one third of preterm labour as potentially treatable (Keirse and Kanhai 1988). Besides efforts to develop new stronger more specific tocolytic drugs with less side effects, efforts should be made to find new more sensitive ways of predicting preterm labour and/or tools to early recognition of preterm labour. Until there is a breakthrough in the development of new tocolytic treatment strate­ gies the drugs of first choice in preterm labour are betamimetics. New in betamimetic treat­ ment is the development of other dose models to decrease the amount of drug given and/or lower the rate and severity of side effects (Steenhoek 1982, Caritis et al. 1984,1991, Ingels et al. 1985, Holleboom et al. 1987,1993, a1996). When betamimetics are contraindi- cated (severe cardiovascular pathology or insulin depended diabetes mellitus) treatment with prostaglandin synthesis inhibitors can be used but only during short time (max. 48 hours) and before 32 weeks of gestation.

49

CHAPTER 4

A LOADING-DOSE INFUSION SCHEME FOR INTRAVENOUS TOCOLYSIS WITH RITODRINE: A PILOT STUDY

51 Chapter 4 A LOADING-DOSE INFUSION SCHEME FOR INTRAVENOUS TOCOLYSIS WITH RITODRINE: A PILOT STUDY

C.A.G. Holleboom', J.M.W.M. Merkus1 and L.W.M. van Eiferen2

1 Department of Obstetrics and Gynecology, Marta Hospital Tilburg, The Netherlands 2 Department of Clinical Research Duphar Nederland BV, The Netherlands

Eur. J. Obstet. Gynecol. Reprod. Biol. 1987; 26: 119-126

SUMMARY

A loading-dose infusion scheme for intravenous ritodrine therapy was tested in twelve patients with preterm labour. We started with a rather high (386 μg/min) infusion rate, but the moment tocolysis was reached this infusion rate was reduced to a level needed to maintain the plasma concentration then found. Plasma samples of ritodrine were taken the moment tocolysis was reached and in the steady state, and compared with each other and with expected and calculated plasma concentrations. In the dynamic loading phase we found a half-Ufe for ritodrine of 1 hour. This half-life of 1 hour can be explained by cumu­ lation of ritodrine in the central compartment and is therefore called cumulation r1/2. In de­ veloping an infusion scheme with a loading dose for ritodrine, this cumulation tw of 1 hour should be taken into account.

Cumulation t1/2, Rilodnne plasma level

See also appendix 1, pp 147-149

52 A PILOT STUDY

Introduction

Beta-2-sympathomimetics are potent drugs designed to reduce uterine activity. They are used worldwide in preventing preterm labour (Barden et al. 1980). Usually the initial the­ rapy is started intravenously (Barden et al. 1980, Keirse 1984). All currently applied intra­ venous dose regimens are empirical, and a rational dosage scheme based on plasma con­ centrations and related to the pharmacokinetic properties of the beta-mimetic drug has not been developed until now.

Table 1 Ritodrine dosage protocol

Initial infusion rate: 386 μg/min

tocolysis after reduce dosage to

0-45 min 97 μg/min 46 min-1 h 15 min 144 μg/min 1 h 16 min-2 h 193 μg/min 2 h-3 h 241 μg/min 3 h-4 h 288 μg/min 4 h-6 h 336 μg/min 6 h-10 h 386 μg/min

Initially a parental fixed dose regimen was applied (Wesselius-de Gasparis et al. 1971), but this has now largely been replaced by an incremental dosage scheme (Barden et al. 1980). With this incremental dosage scheme a low initial dose is increased every 10-15 minutes with a fixed dose until uterine contractions stop or unacceptable side-effects devel­ op. In general, at cessation of uterine activity the infusion rate is maintained. However, due to the pharmacokinetic properties of these drugs the plasma concentration will subse­ quently increase above the level reached at that time, leading to more frequent and serious dose-related side-effects (Steenhoek 1982). To avoid this overdose we tried to develop an infusion scheme starting with a rather high intravenous infusion rate of ritodrine (386 μg/min) until contractions disappeared, subsequently reducing the infusion rate to the level needed to maintain the concentration reached at that time. To test the validity of this infusion scheme we compared plasma concentrations found at the moment of tocolysis with plasma concentrations in the steady state. An abstract of this study has been publish­ ed (Holleboom and Merkus 1986).

Pharmacokinetic background

The rise of the plasma level of a drug, when given by intravenous infusion, is shown in Fig. 1. After the start of the infusion the concentration rises until the steady state is reached. The height of the plasma level depends on the pharmacokinetic properties of the drug, such as its distribution volume (V\) and its elimination rate constant (KJ as well as the infusion rate (R) and the lapse of time after the start of the infusion (f).

53 Chapter 4

1/2 Css—-,

ut Vi

Fig. 1. Build-up of the blood level of a drug given by intravenous infusion. t,a = half-life of the drug; C, = steady-state con­ centration; R = infusion rate.

The blood concentration C, (mg/ml) can be expressed by means of the following equation [5]:

R C, = (1-е**) (1)

The elimination rate constant is related to the drug half-life (t1/2) according to

0.693

Ke =

In the steady state, t is large as compared to t,/2, which gives:

R С = VoK

In this steady-state situation the concentration of the drug (CJ is determined by the infu­ sion rate (R) and the clearance ( цК,,). The above is valid for drugs with first-order kinetics (the majority) and an open one-compartment model. Eqn. 1 can be turned into:

ί

C, =Cm (1-е*«—)

If, for instance, the time after the start of the infusion (t) ί is equal to tll2 of the infused drug ( =1), the corresponding

'l /2 plasma concentration is:

0 3 C< = *w = Cm . 0.5 because (e " = 0.5)

From this it can be calculated that after one tU2/ 50% of the final steady state is reached; after

54 A PILOT STUDY

two tin it is 75%; after three tul 87.5%, etc. Similarly, the steady-state concentration (about 96.9%) is almost reached after a period of approximately 5-times the half-life of the drug. Should this model be applied to the inhibition of labor with beta-2-sympathomime- tics, the desirable infusion rate can be determined from the uterine activity and the dura­ tion of the infusion.

Patients and procedures

Twelve healthy patients in preterm labour, mean gestational age 208 ± 30 (SD) days (see Table II), were treated intravenously with ritodrine according to the protocol after giving their informed consent for participation in the study. Adequate plasma samples could not be obtained from three patients. Preterm labor was defined as more than 10 uterine con­ tractions in 30 min before the 36th week of gestation. All patients were healthy and none of them had used beta-mimetics during pregnancy. Besides ritodrine and bed-rest no other treatment had been given.

Table 2 Characteristics of the 12 patients (means ± S.D.)

η Age(yr) 28.6 ± 4.3 12

Weight (kg) 58.1 ± 7.6 11 Height (cm) 167 + 8.1 10 Gestational age (days) 208 ± 30 10 ...Range 159 + 241 Bishop score 3.5 ± 1.7 11 Tocolysis index (Baumgarten) 2.6 +1.2 11

Fifty mg ritodrine (5ml) were dissolved in 45 ml 5% glucose (1 mg/ml) and admi­ nistered by an infusion pump (Razel, type A99, flow-rate 1.43-30 μΐ/h). The infusion was started at a level of 386 μg/min ritodrine and reduced according to the protocol when no contractions were observed for more than 15 min (see protocol). This lower dosage was unchanged for at least 48 h. The infusion scheme is based on the reported elimination half- life (f1/2) for ritodrine of 2 h (Gandar et al. 1980). Blood samples were taken both when tocolysis was reached or 2 h after starting the infusion (C,) and in the expected steady state (CJ (20-24 h after reducing the infusion rate). Ten ml of blood were taken from the cubital vein opposite the infusion arm, heparinized and centrifuged (300 rpm) and the supernatant was stored at -20° С until the time of analysis. The ritodrine plasma levels were measured at the Duphar Research Laboratories, Weesp, The Netherlands, by the radioimmunoassay method, previously published by Gandar et al. (1980) and Thomas et al. (1982). No information on the infusion rate used was available in the laboratory. The sensitivity of this RIA is 0.1 ng/ml, cross-reaction with ritodrine metabolites 0.2% and coefficient of variations 4.1%. Pharmacokinetic calculations were done with the above men-tioned formulae. Statistical evaluation was performed with Pearson correlation and Wilcoxon matched-pairs signed-ranks tests. A p-value of 0.05 or less is regarded as being statistically significant.

55 Chapter 4

Results

All patients tolerated the infusion scheme well and no serious side-effects compelling us to change or stop the infusion rate developed. Changes in maternal and fetal heart rate and blood pressure are given in Table III. A change of more than 5 mmHg in systolic and dia­ stolic blood pressure and 10 mmHg in pulse pressure with pretreatment values was regarded as being a significant difference. In the maintenance period no dose adjustments were necessary because uterine contractions did not recur. Tocolysis was achieved in all 12 patients within 8 h and in 9 out of 12 patients with­ in 1.30 h (Table Г ). This means that to maintain tocolysis 9 out of 12 patients required less than 200 μg/min ritodrine.

With the measured plasma concentrations in the starting phase (C¿) and steady-state concentrations (CJ a tV2 of 50 + 20 min was calculated (Table V). This half-life of 50 + 20 min is not the same as the elimination t1/2 of 2 hour used in our dosage scheme. This is probably a result of distribution from central to peripheral com­ partments and elimination processes. The tw reflects the pharmacodynamics of ritodrine in the loading phase of the infusion and is called by us the cumulation tm.

Table 3 Pretreatment and maximum values during treatment in the first 6 h of maternal heart rate (MHR), fetal heart rate (FHR), systolic blood pressure, diastolic blood pressure and pulse pressure in relation to time of occurrence after starting the infusion (t^J.

Pretreatment During first 6 h of treatment (n = 12) Max. values t^ (min)

MHR (beats/min) mean+SD 89+17 126±20 ' 52+37 range 60-116 80-150 5-120 FHR (beats/min) mean+SD 144±13 168±15 ' 82±64 range 120-160 140-200 15-240 Systolic BP (mmHg) mean+SD 124±15 140±14a 20 b±ll range 105-155 120-170 5-30 Pulse pressure (mmHg) mean+SD 46+11 68+12a 36 422 range 30-65 50-85 10-90 Diastolic BP (mmHg) mean+SD 78+9 60+9 a 56±32 range 60-95 40-75 15-120 Dose adjustment mean+SD 124+151 range - - 13-480 a Significantly different from pretreatment (p<0.005). b Significantly before dose adjustment (p<0.05).

56 A PILOT STUDY

Table 4 Time elapse before tocolysis and dose adjustments.

Patient No. Tocolysis reached after (min) Dosage to ^g/min)

1 13 97 2 25 97 3 29 97 4 33 97 5 36 97 6 lhll 144 7 Ih 36 193 8 3h 5 386 9 8h 193 11 45 97 12 6 h 20 336

Table 5

Concentration at moment of tocolysis (Ct), measured steady-state concentration (CS5), cal­ culated steady-state concentration for t„2 = 2 h (Css1l/2 = 2 h), calculated steady-state con­ centration for tm = 1 h (С„Лт = 1 h) and cumulation f^.

Patient c, Calculated Measured Calculated Cumulation No. (ng/ml) CAn = 2h C :t = 1 h fl/2 с. ss ll2 (ng/ml) (ng/ml) (ng/ml) (min)

1 22 78 34 40 50 2 35 66 43 36 74 3 100 163 50 88 29 4 37 54 32 30 65 5 64 86 24 47 23 6 47 53 34 32 67 7 96 112 71 71 59 8 84a 105 51 70 21 9 89 a 126 98 97 63 Mean+SD 64+29 94±36 49±23 57±25 50±20

' Plasma samples taken 2 h after start of the infusion.

The cumulation tm is the time needed after starting the infusion to reach half of the steady-state concentration without changing the infusion rate. As a result of the discre­ pancy in t„2 the measured plasma concentrations in the steady state (Си = 49 + 23 ng/ml) were lower than the calculated Cs for tip = 2 h (see Table V). Comparison of calculated Си for tI/2 = 1 hour with measured Css revealed a good correlation. Correlation coefficient г = 0.81 (Pearson), significance p<0.01 (Fig. 2).

57 KO- Css cale ng/ml RITODRINE

Τ 1 1 1 1 1—ι 1 1 1 20 АО 60 80 100 Css measured ng/ml

Fig. 2. Correlation between measured and calculated steady-state concentrations for tm = 1 hour.

Discussion

The incremental dosage scheme used for intravenous tocolysis with beta-2-mimetics leads to overdose (Fig. 3). This is inherent in the scheme, because the contractions disappear before the steady-state concentration for that infusion rate is reached. It is better to reduce an initially fixed infusion rate to a dose level needed to maintain the effective concentra­ tion reached at that moment (Ingels et al. 1985, Smit et al. 1984, Steenhoek 1982).

Fig.3. Overdose given after tocolysis is achieved at time A. Сл = plasma concentration reached at time A with infusion rate R C, = steady state concentration reached with infusion rate R

Ingels et al. (1985) found steady-state concentrations of ritodrine after 2 h of infusion instead of the expected 6-8 h; Post (1977) also observed this phenomenon. This is a conse­ quence of cumulation of ritodrine in the central compartment.

58 A PILOT STUDY

We studied an infusion scheme for ritodrine based on the reported half-life of 2 hour (Gandar et al. 1980). Evaluating the results the cumulation tw was 50 + 20 min rather than the reported elimination tw of 2 h. This explains the difference in calculated and measured steady-state concen- tracions and in effective and measured steady-state concentrations. We observed interindividual differences in cumulation tV2 (21-74 min) which could have been due to individual differences in metabolism. The influence of pregnancy on ritodrine metabolism is not completely clear. Changes in liver metabolism, renal clearan­ ce, compartment and volume enlargement all play a role (Bogaert and Thiery 1983). The infusion scheme used in our study takes these inter-individual differences into account: the infusion rate is reduced after contractions have disappeared and not after a fixed time. The degree to which the infusion rate is reduced is based on the pharmacokinetic conside­ rations mentioned above. Further studies are needed in order to conclude whether reduc­ tion of the infusion rate with a scheme based on accumulation tm = 1 hour is feasible. Besides the lower risk of an excessively high plasma concentration, another advan­ tage of the infusion scheme studied is that fewer dose adjustments are necessary (only to reduce the infusion rate at time of tocolysis), which also leads to fewer side-effects. Side- effects depend not only on the absolute concentration of ritodrine; the rate of change in the infusion rate or drug concentration may be more important (Caritis et al. 1983). Finally, by using a high loading-dose, effective plasma concentrations are achieved more rapidly than with the incremental dosage scheme, so the intended effect (tocolysis) can be expected ear­ lier.

Conclusions

The proposed dosage scheme for intravenous ritodrine is in practice well-accepted by patients and needs very few dose adjustments. Instead of the reported elimination f,/2 of 2 hour a cumulation tV2 of 1 hour should be used in developing a loading dose infusion sche­ me. This infusion scheme makes it possible to reach and maintain the minimal effective dosage in the individual patient. A new study with an infusion scheme based on the cumulation t,/2 of 1 hour is in progress.

Acknowledgements

We wish to thank L.W. de Zoete of the Duphar Company, Weesp, The Netherlands, for the determination of the ritodrine plasma concentrations by the RIA methodology.

59 60 A LOADING MODEL FOR RITODRINE ADMINISTRATION IN PRETERM LABOUR Chapter 5 A LOADING MODEL FOR RITODRINE ADMINISTRATION IN PRETERM LABOUR

C.A.G. HOLLEBOOM, J.M.W.M. MERKUS, L.W.M. VAN ELFEREN, and M.J.N.C. KEIRSE

Department of Obstetrics and Gynaecology, María and Elizabeth Hospital, Tilburg, The Netherlands C.A.G. HOLLEBOOM J.M.W.M. MERKUS Department of Clinical Research, Duphar Nederland, Amsterdam, The Netherlands L.W.M. VAN ELFEREN Department of Obstetrics, Gynaecology and Reproduction, Leiden University Hospital, Leiden, The Netherlands M.J.N.C. KEIRSE

Br. J. Obstet. Gynaecol. 1993; 100: 1107-1110

ABSTRACT

Objective - To develop a ritodrine infusion scheme for preterm labour, that (a) avoids plas­ ma levels above those needed for tocolysis, (b) requires only one rate adjustment, and (c) is easy to apply in practice.

Design - Prospective study of tocolytic effect and plasma ritodrine concentrations during application of the infusion scheme.

Setting - High risk labour ward.

Subjects - Consecutive series of 31 women in labour at <36 weeks' gestation.

Intervention - Loading dose ritodrine infusion followed, as soon as tocolysis is reached, by a decrease in the infusion rate calculated on the basis of the interval between start of treat­ ment and tocolysis.

Results - Overall, steady state ritodrine levels were nearly identical to those at the time of tocolysis and correlated well with levels anticipated on the basis of our calculation (r=0.91; p<0.001; n=30). Adjustments during steady state were made in 12 women (40%), but in only 2 of them within 12 hrs after tocolysis had been reached. Delivery was post­ poned for >48 hours in 29 women (93.5%) and beyond 37 weeks' gestation in 19 (61.3.%).

Conclusion - The loading model is easy to apply, avoids relative overdoses, requires few adjustments, is well tolerated, uses smaller quantities of ritodrine, and results in lower plasma ritodrine concentrations than the conventional infusion scheme.

62 A LOADING MODEL FOR RTTODRINE ADMINISTRATION IN PRETERM LABOUR

Introduction

Betamimetics have been shown to be effective for inhibiting preterm labour (King et al. 1988). Most of the evidence relates to ritodrine, which is usually administered intrave­ nously in increasing doses until uterine quiescence is achieved or until side effects prohi­ bit further increments. This approach results in plasma levels, which continue to increase after the effective infusion rate is reached (Smit et al. 1984) and, thereby, augment the risk of side effects and complications. We, therefore, designed a ritodrine infusion regimen that avoids plasma levels in excess of those needed to achieve uterine quiescence. It was based on the hypothesis that the appropriate infusion rate could be calculated from an initial loading dose and the inter­ val between the start of treatment and initial cessation of contractions.

Patients and Methods

A consecutive series of 31 healthy women in preterm labour (defined as regular contrac­ tions less than 8 minutes apart) requiring betamimetic tocolysis before 36 weeks' (mean: 206 (SD 33) days) consented to participate in the study. Seven had ruptured membranes and none had been given tocolytics previously. Ritodrine (1 mg/ml in 5% glucose) was administered by an infusion pump at an ini­ tial rate of 200 μg/min. If tocolysis was not reached within 2 hours, the rate was increased to 400 μg and eventually to 600 μg/min, if contractions remained for a further 2 hours. As soon as contractions remained absent for more than 10 minutes, the infusion rate was adjusted according to the schedule in Table 1. The new infusion rate was kept unchanged for 48 hours unless contractions recurred in which case infusion was readjusted to the rate that had achieved tocolysis. The infusion regimen (Table 1) was based on a deliberate simplification of pharma­ cokinetic properties and on the known cumulation half-life time of ritodrine (Holleboom et al. 1987) with the formula:

t(ú IRSS = IRt0} - (троо χ 2- /t1/2aiJ (formula 1)

This formula itself was derived from assuming identical ritodrine levels at tocolysis and in steady state (i.e. C, = С J in the equations (used to calculate expected plasma ritodrine con­ centration during steady state) below. The equations refer to concentrations achieved at tocolysis with 200 μg/min (formula 2a) and 400 μg/min (formula 2b).

С С t200 Ct = — x (IRtM - [IRp^c χ 2- /tll2mJ) = — χ 'A'

IRSS IRSS (formula la)

г ss

Ct = χ I ('A'χ 2-WrtI/2nJ + (IRttM - [IRtm χ r^ty^J)}

IRSS (formula 2b) 63 Chapter 5

In these equations: C, = ritodrine concentration at the time of tocolysis before changing the initial infu­ sion rate;

C№ = ritodrine concentration in the steady state after adapting the infusion rate; IRB = infusion rate adapted after reaching tocolysis (i.e. infusion rate in steady state); IR, = infusion rate with which tocolysis was achieved; t = duration of the infusion at its current rate until initial tocolysis is obtained or

120 min. if no tocolysis is obtained with the current infusion rate (t200/1^, and t,,

refer to the durations of infusions at respectively 200 μg/min/ 400 μg/min, and any rate). ti«™™ = ritodrine cumulation half-life time (chosen as 60 min for the calculation of IR^ in formula 1);

Blood samples were taken at the time of tocolysis and again at 2, 12-24, and 36-48 hours after the infusion rate was adjusted and kept unchanged. Ritodrine concentrations were measured in coded study and randomly added control samples by high pressure liquid chromatography with electrochemical detection (Lin et al. 1984). Measured and calculated (formula 2) ritodrine steady state concentrations were compared with linear regression analysis. Other statistics used were paired t-test, linear regression and ANOVA for analysis of variance of the model.

Table 1 Regimen used for ritodrine administration starting with a loading dose infusion rate of 200 μ^ιηίη.

Tocolysis achieved Adapt dose to

within (hours) (\ig/mm)

Sfori infusion with 200 ц%Ітіп λΑ 50 XA - 1 100 1 - VÁ 150 VÁ - 2 200 No tocolysis within 2 hours: increase to 400 uglmin 2 - TA 250 TA - 3 300 3 - УА 350 3% - 4 400 No tocolysis within 4 hours: increase to 600 \ig¡mm 4 - 4M 450 Ш - 5 500 5 - 5JÍ 550 5A - 6 600

64 A LOADING MODEL FOR RITODRINE ADMINISTRATION IN PRETERM LABOUR

Fig 1 RUodnne plasma concentrations (mean and SEM) in ng/ml at the time of initial tocolysis (=t) and in the steady state period at a mean time of 2 (=t,), 18 (=t,), and 40 (=tj hours after dose adjustment to steady state infusion rates of 50 μg/mm

(1R¡J, 100 p.g¡min (IR1C0), and 150 ugimin ffl?J5J and without dose adjustment (IRm, continuous infusion of 200 \ig\min) Only the measurements from women in whom all 4 samples were obtained at the appropriate times are included Statistical differences with levels obtained at time t are indicated by * for ρ <0 05, and by "for ρ <0 005 Further details can be ob­ tained from the authors

С I ι I I I , 0 20 40 60 80 100 120 ng/ml calculated

Fig 2 Conelation between measured and expected steady state plasma ritodnne concentrations (CJ for all women in whom initial tocolysis was achieved (y = 0 97x -1 6,r = 0 91, ρ <0 001, η = 30) Expected concentrations were calculated from the formulae 2a and 2b in the Patients and Methods' section using the measured f'to„ of 50 minutes Further details can be ob­ tained from the authors

65 Chapter 5

Results

The infusion scheme was well tolerated by all women; none developed side effects com­ pelling a change in infusion rate. In all but two women, the initial infusion rate of 200 μg/min achieved tocolysis within 2 hours. One woman with ruptured membranes achie­ ved no tocolysis and she delivered within 24 hours. Another woman achieved tocolysis at 400 μg/min after 2.5 hours and the infusion rate was then adjusted to 250 μg/min (Table 1). Delivery was postponed for >48 hours in 29 women (93.5%), until 36 weeks in 23 (74.2%) and until 37 weeks in 19 (61.3%). There were no perinatal deaths. The mean steady state infusion rate to maintain tocolysis was 119 (SD 61) μg/min (range 50 - 250 μg/min; η = 30). Dose adjustments during the steady state were necessary in 12 women (40%) because uterine contractions recurred, but in only 4 women (13%) did this occur within 36 hours after adjusting the dose. Only two (7%) required adjustment within 12 hours of reaching the steady state. The average plasma ritodrine level in the 30 women, in whom contractions ceased, was 40 ng/ml (SEM 3). Overall, this level remained remarkably constant after adopting the steady state infusion rate. Mean (SEM) levels at 2,12-24, and 36-48 hours after dose adjust­ ment in all women were respectively 36 (3), 39 (5), and 42 (5) ng/ml. When analyzed according to steady state infusion rates (Fig. 1), ritodrine concentra­ tions during infusion of 50 μg/min were significantly lower than at initial tocolysis (p <0.05), but only one woman needed a higher dose within 36 hours. With steady state infu­ sions of 100 and 150 μg/min, levels at initial tocolysis and during steady state were near identical. Levels during unadjusted, continuous infusion of 200 μg/min showed an ex­ pected, gradual increase (Fig. 1). Women whose infusion was reduced to 50 or 100 μg/min had similar ritodrine levels at initial tocolysis (32 vs. 36 ng/ml; Fig. 1), although the time to reach tocolysis was twice as long in the latter group (31 vs. 67 min). Steady state concentrations of ritodrine at infusion of 50 μg/min were half those at infusion of 100 μg/min, one third of those at 150 μg/min and about one quarter of those at 200 μg/min ritodrine (Fig. 1). Mean (SEM) con­ centrations at 36-48 hours for each of these infusion rates (n = 6-8) were respectively 20 (1), 39 (3), 59 (8), and 73 (3) ng/ml. The mean ritodrine cumulation half-life time, used in formula 2 to calculate steady state concentrations, was 50 min (SD 27.8; η = 30). Regression analysis of all matched cal­ culated and measured steady state concentrations showed a good correlation (y = 0.97x + 3.8; r = 0.87; ρ <0.001; η = 81). A similar relation was observed between mean measured concentrations per woman (Fig. 2) and calculated values (y = 0.97x - 1.6; r = 0.91; ρ <0.001; η = 30; Fig 2).

Discussion

Our purpose was to develop a regimen that would fulfil the following criteria: (a) readily applicable in clinical practice; (b) no increase in plasma ritodrine concentrations once toco­ lysis is reached; (c) as few dose adaptations as possible; and (d) a lower total amount (and cost) of drug use. The formula used for this purpose was based on an assumption of first order kine­ tics and one-compartment distribution of ritodrine. This is a gross simplification of the true pharmacokinetics of ritodrine (Gandar et al. 1980; Caritis et al. 1983), but it was necessary to obtain a simple clinical measure for estimating the infusion rate needed. The time inter-

66 A LOADING MODEL FOR RWODRINE ADMINISTRATION IN PRETERM LABOUR val between start of treatment and cessation of contractions provides such a measure and it appeared workable in practice. Overall, average ritodrine levels at different time points during steady state were equivalent to those at initial tocolysis. The basis of our regimen is the cumulation half-life time of ritodrine, which was known to average 50 min (Holleboom et al. 1987) and was confirmed in the current investigation. Obviously, there is individual variation in this cumulation half-life time as can be seen from the relationship between measured and calculated levels in figure 2. This variation around the mean 50 min. cumulation half-life time measured allowed us to choose the easier 60 min. measure for the clinical purpose of dose adjustments. As our results indicate, the clinically more convenient, half-hour intervals (Table 1) obtained in this way were adequate for the pur­ pose of dose adjustment. The benefits of this infusion scheme are: it results in lower ritodrine concentrations than conventional infusion schemes, overdoses are avoided, and few changes in infusion rate are needed. These are important in reducing side effects, since side effects relate not only to infusion rates and plasma concentrations, but also to changes in them (Caritis et al. 1983 & 1984). We found the maximal changes in blood pressure and heart rate within 90 min after starting treatment and the magnitude of change was independent of the steady state infusion rate (data not shown). This appears to confirm that side effects relate as much to changes in ritodrine levels as to the ultimate level achieved (Caritis et al. 1983 & 1984). Also the risk of pulmonary oedema, which relates to the amounts of fluid and drug administered (Keirse et al. 1989), should be lower with a regimen that reduces the total amount of ritodrine administered. A disadvantage of the regimen used is that dose adjustments during steady state infusion were made in 40% of the women. This disadvantage is more apparent than real, however, since readjustment was required only twice within 12 hours. Most readjustments (75%) were made after ritodrine had been infused for >36 hours. This suggests that mecha­ nisms, such as additional labour-initiating stimuli or myometrial desensitisation to beta- mimetics (Harden 1983; Caritis et al. 1987), played a larger role than an inappropriate steady state infusion rate. It also indicates that, for the large majority of women, uterine quiescence can be maintained without further dose adaptation for as long as is necessary to receive maximal benefit from antenatal corticosteroid administration (Crowley et al. 1990). While our loading model offers major advantages over existing systems of betami- metic drug administration in preterm labour, it remains uncertain whether it will result in improved mother and infant outcomes. A multicentre randomized comparison between the loading model and conventional ritodrine administration is currently being conducted to investigate this important question.

Acknowledgements

We thank Mr. E. Moerman of the Heymans Institute, University of Gent, Belgium, for the ritodrine measurements.

67

CHAPTER 6

RANDOMIZED COMPARISON BETWEEN A LOADING AND INCREMENTAL DOSE MODEL FOR RITODRINE ADMINISTRATION IN PRETERM LABOUR

69 Chapter 6 RANDOMIZED COMPARISON BETWEEN A LOADING AND INCREMENTAL DOSE MODEL FOR RITODRINE ADMINISTRATION IN PRETERM LABOUR

CA.G. HOLLEBOOM, J.M.W.M. MERJKUS, L.W.M. VAN ELFEREN and M.J.N.C. KEIRSE

Department of Obstetrics and Gynaecology, Bronovo Hospital, The Hague, The Nether­ lands CA.G. HOLLEBOOM Consultant Department of Obstetrics and Gynaecology, St. Radboud Hospital, Catholic University Nijmegen, The Netherlands J.M.W.M. MERKUS Professor Medical Department, Duphar Nederland, Weesp, The Netherlands L.W.M. VAN ELFEREN Scientific Officer Department of Obstetrics and Gynaecology, Flinders Medical Centre, Flinders University Adelaide, Autralia M.J.N.C. KEIRSE Professor

Br. J. Obstet. Gynaecol. 1996; 103: 695-701

Running title: randomized trial of ritodrine regimens in preterm labour

ABSTRACT

Objective - To compare a new loading dose regimen for intravenous ritodrine administra­ tion in preterm labour with the conventional dose regimen.

Design - Multicentre randomised trial using numbered opaque sealed envelopes.

Setting - Five teaching hospitals in the Netherlands.

Participants - Women (n = 203) in preterm labour at less than 34 weeks' gestation.

Interventions - Women received either a loading dose ritodrine infusion followed, as soon as tocolysis is reached, by a decrease in infusion rate or the conventional schedule of in­ creasing doses until uterine quiescence is achieved.

Results - Frequency of successful tocolysis (71%) and duration of treatment (55 hours) were similar in both groups, but the loading dose schedule was better tolerated with fewer ad­ verse events. Also the number of dose adjustments was smaller than in the incremental dose group (p <0.001). Overall, the differences between the two regimens were unexpectedly small.

70 RANDOMIZED TRIAL OF RLTODRINE REGIMENS IN PRETERM LABOUR

Conclusion - Despite the small differences, the loading model is easier to apply, requires fewer dose adjustments, is better tolerated with less side effects, and reduces the likelihood of clinical error.

Introduction

Classically, ritodrine, the most commonly used betamimetic agent for treatment of preterm labour (Lewis et al. 1980; Keirse 1984), is administered intravenously in stepwise incre­ mental doses until uterine quiescence is achieved or side effects preclude further increases. This approach results in a gradual increase in plasma ritodrine concentrations that con­ tinues even after an effective infusion rate has been reached (Smit et al. 1984). Because adverse effects are related to both total dose and dose changes (Caritis et al. 1983 & 1984) we designed a loading dose schedule with two main characteristics (Holleboom et al. 1993). It avoids doses in excess of what is needed to achieve and maintain uterine quies­ cence and it requires only one or two adjustments of the infusion rate to reach an effective minimal infusion rate (Holleboom et al. 1993). We now report on a multicentre randomised study in which the new loading dose regimen was compared with the conventional system of ritodrine administration for treat­ ment of preterm labour.

Participants and methods

Five teaching hospitals participated in this 4 years' study (shorter at some hospitals) after ethical approval of a protocol that consisted of two parts. The first part, which is reported here, consisted of a randomized comparison between the loading dose (LD) and a con­ ventional incremental dose (ID) regimen for intravenous ritodrine administration in pre­ term labour. The second part, which is reported separately (Holleboomb et al. 1996), was a double-blind, placebo-controlled evaluation of sustained release ritodrine capsules for maintaining uterine relaxation in those women whose preterm labour had been arrested by these treatments (fig. 1). Irrespective of whether they had received the LD or the ID schedule, women participating in the second part had an equal chance of being allocated blindly to placebo or sustained release ritodrine capsules. This implies that the influence of maintenance treatment (active or placebo) on neonatal outcome will be unbiased and similar for both the LD and ID schedules (fig. 1).

Women in preterm labour allocated to receive ritodrine by І i Loading dose regimen Incremental dose regimen 1 1 1 i Failure Success Success Failure 1 i 1 1 1 Candidates for maintenance trial 1 I 1 Non- Pia Rit Rit Pia Non- participants participants i _1_ Χ Χ J_ J_ Outcome loading dose Outcome incremental dose

Fig. 1. Schematic representation of the study protocol (Pia = placebo; Rit = ritodrine).

71 Chapter 6

A consecutive series of 203 healthy women in preterm labour, requiring tocolysis with betamimetics because of £ 3 regular contractions per 15 minutes and/or an increase in cervical dilatation before 34 weeks' gestation, participated in this study. After informed con­ sent, women were allocated at random by numbered, opaque, sealed envelopes to either one of two treatment groups. Two additional envelopes were drawn erroneously for women who failed to meet the entry criterion of labour before 34 weeks and seven for women who had exclusion criteria, such as earlier tocolytic treatment in the current preg­ nancy (n = 4) or a diagnosis of intrauterine infection (n = 1), fetal anomaly (n = 1), or full dilatation (n = 1) before randomisation. These 9 women were considered as non-partici­ pants prior to any assessment of outcomes. Recruitment was stopped when the predetermined sample size of 200 women was known to have been achieved at the 5 centres. This sample size has an 80% power of detec­ ting a 20% difference in the frequency of successful tocolysis between the two treatment groups (a = 0.05) Women allocated to the experimental arm (loading dose; LD; η = 101) received a loading dose of 200 μg/min ritodrine until tocolysis was reached whereupon the infusion rate was reduced in a standard fashion calculated from the interval between start of the treat­ ment and tocolysis (table 1). The conventional (incremental dose; ID; η = 102) treatment consisted of a dose of 50 μg/min ritodrine that was increased with 50 μg/min about every 15 min until uterine quiescence was reached or until side effects prohibited further dose increases. Both treatments were administered with an infusion pump. After cessation of uterine contractions, treatment was continued for 24 to 48 hours in both groups. Thereafter, the dose was reduced to a maintenance level of 50 μg/min for 12-24 hours whereupon oral maintenance treatment was started. The latter consisted of either placebo or sustained release capsules of ritodrine (240 mg daily), in a double-blind fashion, for 7 days (Holleboom1· et al. 1996). Treatment, whether intravenous or oral, was stopped in the event of severe side effects, signs of intrauterine infection or fetal distress, and imminent delivery. The use of other tocolytic drugs was not allowed unless clinically indicated because of failure to respond to ritodrine treatment alone. All other concurrent medication was restricted with the exception of corticosteroid administration for fetal lung maturation which was recommended. The main outcome parameter was successful tocolysis defined as the end of intra­ venous treatment in the absence of progressive labour or achievement of 34 weeks of gesta­ tion, whichever occurred first. Additional predefined outcomes were: the total dose of ritodrine administered, the duration of intravenous treatment until tapering off, infusion rates of ritodrine 12, 24, and 48 hours after start of treatment, and the number of dose adjustments in the first 12, 24 and 48 hours of treatment. Assessments of safety and tolerance were made on the basis of adverse events, dose adaptations prompted by side effects, and changes in fetal heart rate, maternal heart rate and blood pressure between the start of the infusion and the first few hours of treatment. Plasma concentrations of sodium, potassium, chloride and bicarbonate were measured at the start of treatment and 8-16 and 24-40 hours afterwards. Before analysis, all data entry sheets were assessed by one of us (MJNCK), blinded to treatment allocation and neonatal outcome. Statistical analysis was performed in the SAS analysis system using Student's t-test, Wilcoxon two sample test and the χ2 or Cochran-Mantel-Haenszel χ2 tests. The CIA programme (British Medical Journal, version 1.0; Gardener and Airman 1989) was used for confidence interval analysis.

72 RANDOMIZED TRIAL OF RITODRINE REGIMENS IN PRETERM LABOUR

Table 1 Regimen used for ritodrine administration starting with a loading dose infusion rate of 200 ц^тіп.

Tocolysis achieved Adapt dose to

within (hours) ^g/min)

Start infusion with 200 ця/тіп гА 50 И 1 100 1 154 150 VA - 2 200 No tocolysis within 2 hours: increase to 400 \iglmin 2 2И 250 TA - 3 300 3 УА 350 УА - 4 400 No tocolysis within 4 hours: increase to 600 uglmin 4 4A 450 4A - 5 500 5 5JÍ 550 5XA - 6 600

Table 2 Characteristics of women participating in the trial

Characteristic Loading dose Incremental dose Ρ value* (n = 100) (n = 101)

Duration of pregnancy at trial entry no. < 28 weeks 8 5 no. < 32 weeks 51 48 days: mean (SD) 217 (15) 219 (15) 0.271

Prelabour rupture of the membranes 16 14 0.672

Multiple pregnancy 10 9 0.792 twin pregnancy 9 8 triplet pregnancy 1 1 Tocolytic index: mean (SD) 3.9 (1.8) 3.7 (1.7) 0.433

Bishop score: mean (SD) 4.5 (2.3) 4.8 (1.9) 0.363

1 2 2 3 * Statistical test used: t test, χ test, Cochran-Mantel-Haenszel

73 Chapter 6

Table 3 Characteristics and main outcomes of the two treatment schedules

Characteristic Loading dose Incremental dose Ρ value* (n = 100) (n = 101)

Mean infusion rates in ^g/min (SEM) at 12 hours 151 (11) 166 (9) 0.081 at 24 hours 152 (11) 154 (8) 0.271 at 48 hours 159 (15) 165 (11) 0.25'

Treatment until tapering off: mean (SEM) Total dose of ritodrine (mg) 573 (97) 552 (67) 0.321 Duration in hours 59 (8) 52 (4) 0.7Γ

No. of infusion rate adjustments within 12 hours: mean (SEM) 0.9 (0.08) 2.3 (0.16) <0.0012 between 12 and 24 hours (SEM) 0.2 (0.06) 0.2 (0.05) 0.7Γ within 24 hours: mean (SEM) 1.1 (0.11) 2.4 (0.20) <0.0012

Tocolytic effect 0.912 Success 68 69 Partial success 4 2 Failure 25 25 Not ascertainable 3 5

No. of women with changes in infusion rate because of side effects 0.022 warranted increase impossible 5 6 infusion rate reduced 2 9 infusion stopped 0 1

Delivery within 12 hours 9 6 0.433 between 12 and 24 hours 4 7 0.373 between 24 and 48 hours 6 5 0.773 < 32 weeks 20 21 0.893 32 - 33 weeks 17 16 0.853 34 - 36 weeks 24 16 0.11' mean gestational age (days; SEM) 248 (2.7) 250 (2.7) 0.594

* Statistical test used: ' Wilcoxon test,2 Cochran-Mantel-Haenszel,3 χ2 test,4 f test

74 RANDOMIZED TRIAL OF RITODRINE REGIMENS IN PRETERM LABOUR

Results

In the 5 participating centres 212 envelopes were drawn for the 203 participants and 9 non- participants. Two women were excluded from the analysis; one in the LD group because of lost case records and one in the ID group because she was erroneously started on the loading dose and was therefore withdrawn from the study by her obstetrician. Both women gave birth to live infants who survived. The overall evaluation was performed on the data of the remaining 201 women of whom 100 had been allocated to the experimental (loading dose; LD) schedule and 101 to the conventional (incremental dose; ID) schedule. The groups did not differ statistically in terms of age, gestational age, number of twins and triplets, Bishop score (Bishop 1964), tocolytic index (Baumgarten & Grüber 1974), and incidence of ruptured membranes (table 2). Ninety-five women (47 %; 50 from the LD group and 45 from the ID group; n.s.) subse­ quently participated in the double-blind maintenance trial (fig. 1). The loading dose schedule was always administered according to protocol (table 1), but the incremental dose schedule was started with 100 μg per min in 7 women and in only 30% of the women (n = 32) was the time interval for dose augmentations strictly observed at 15 minutes; in the others the interval was longer at 20 (n = 34) or even 30 min (η = 30). This was because the participating clinicians were used to be more cautious with the con­ ventional infusion scheme often applying it in a more gradual way than officially prescrib­ ed. We accepted this as normal variation within the confines of clinical practice. Successful tocolysis was defined as arrest of intravenous treatment in the absence of progressive labour or at reaching a gestational age of 34 weeks. Tocolysis was con­ sidered to be only partially successful if another agent (always indomethacin) had been co-administered at some stage. The incidences of successful tocolysis, partial success and failure were similar in both groups (table 3). In 8 women treatment was stopped becau­ se of suspected intrauterine infection (n = 4), abruption (n = 2) or fetal distress (n = 2), rendering an assessment in terms of successful or failed tocolysis meaningless (not ascer­ tainable; table 3). The total amount of ritodrine used up to the start of tapering off did not differ between groups (table 3). Also the mean infusion rates in μg/min at 12, 24 and 48 hours after start of treatment were similar as was the duration of intravenous treatment until the start of maintenance (table 3). Statistically there was a highly significant difference in the number of dose adjustments in the first 12,24 and 48 hours of treatment (Cochran-Mantel- Haenszel, ρ <0.001; table 3). Side effects (table 4) precluding further dose increments or prompting a lowering or even arrest of the infusion occurred significantly more often in the ID group (Cochran-Mantel-Haenszel, ρ = 0.02; table 3). Starting with the relatively high loading dose (200 μg/min) in the LD group caused fewer complaints and side effects, than the low starting dose of the incremental scheme (50 μg/min) which had to be upgraded several times. In only one woman in the ID group was the infusion stopped in the first 12 hours because of severe side effects (headache, dizziness, palpitations, tremor, dyspnea, tachycardia, nausea, and agitation); she gave birth within four hours after stopping treatment. In 22 other women (LD: 7; ID: 15) the infusion rate could not be increased or had to be lowered because of side effects (table 3). Changes in serum electrolytes and bicarbonate before and 8-16 and 24-40 hours after the start of treatment did not differ between both groups. The largest change was seen in potassium levels which decreased significantly (p <0.001) from before treatment in the entire group. Changes in chloride, sodium and bicarbonate were not remarkable.

75 Chapter 6

Table 4 Nature and frequency of maternal side effects in the first 12 hours of the loading dose and incremental dose schedules

Moderate or severe Loading dose Incremental dose Difference (%) and side effects (n = 100) (n = 101) 95% confidence interval

Any type of side effect 22 32 -9.6 -21.7 to 2.5

Palpitations 8 16 -7.8 -16.6 to 1.0

Tachycardia 7 8 -0.9 -8.1 to 6.3

Tremor 7 18 -10.7 -19.6 to -1.9

Agitation 4 3 1.0 -4.0 to 6.0

Nausea 5 4 1.0 -4.6 to 6.7

Vomiting 1 4 -2.9 -7.2 to 1.3

Headache 1 3 -2.0 -5.8 to 1.9

Dyspnea 1 1 0 -2.7 to 2.7

Total no. of such side effects 34 57

Maternal heart rate and blood pressure were recorded more frequently in the ID group than in the LD group, because such measurements were often linked to adjustments in the infusion rate which were more frequent in the ID group. There were no statistically significant differences between the LD and ID group in maternal heart rate, increasing respectively with 30 and 27 beats/min, and in fetal heart rate which increased with 14 beats/min in both groups. Changes in or absolute levels of systolic blood pressures were not statistically different between both trial arms. The proportion of women with a drop in diastolic blood pressure was significantly greater in the ID group (LD: 49%; ID: 73%), but the extent of the decrease was similar for both groups. Changes in pulse pressure in both groups were comparable and of negligible clinical importance. The proportions of women delivering before 32, 34 and 37 weeks were similar in both treatment groups (table 3). Including 17 twin and 2 triplet pregnancies each treatment group contains 111 infants with mean birthweights of 2421 ± 784 grams in the LD group and 2570 ± 879 grams in the ID group. There was one unexplained intrauterine death at term in the LD group 8 weeks after stop of ritodrine treatment. Four neonatal deaths occurred in the ID group (table 5); two of these were due to immaturity in a twin pregnancy (25 weeks), one to cord prolapse and one to hydrocephaly. There were no maternal deaths and no instances of pulmonary oedema.

76 RANDOMIZED TRIAL OF RITODRINE REGIMENS IN PRETERM LABOUR

The main neonatal morbidity was respiratory distress syndrome which occurred with equal frequency in both treatment groups (table 5). Periventricular-intraventricular haemor­ rhage was less frequent in the LD group (n = 4) than in the ID group (n = 15; table 5), but a difference in this outcome was not a prior hypothesis of our study. All adverse infant outcomes except admission to neonatal intensive care and hyperbilirubinaemia tended to be more frequent in the ID group than in the LD group (table 5).

Table 5 Perinatal and neonatal outcome after loading dose and incremental dose treatments

Outcome Loading dose Incremental dose Difference (%) and (n = 111) (n = 111) 95% confidence interval

Fetal and neonatal mortality 1 4 -2.7 -6.6 to 1.1

Admission to intensive care 65 60 4.5 -8.5 to 17.5

Reasons for admission* Born too early 51 46 4.5 -8.5 to 17.5 Small for gestational age 15 7 7.2 -0.6 to 15.0 Fetal distress 6 10 -3.6 -10.4 to 3.2 Suspected infection 4 5 -0.9 -6.1 to 4.3 Sepsis 5 7 -1.8 -7.8 to 4.1 Others 13 18 -4.5 -13.6 to 4.6

Respiratory distress syndrome 12 17 -4.5 -13.4 to 4.3 class I or II 11 14 -2.7 -11.0 to 5.6 class > II 1 3 -1.8 -5.3 to 1.7

Patent ductus arteriosus -4.5 -9.1 to 0.1

Periventricular-intraventricular haemorrhage 4 15 -9.9 -17.2 to -2.7 grade I or II 4 12 -7.2 -13.9 to -0.5 grades > II 0 3 -2.7 -5.7 to 0.3

Hyperbilirubinaemia 32 28 3.6 -8.1 to 15.3

* Some infants had several reasons for admission

77 Chapter 6

Discussion

As betamimetic agents are potent drugs that can cause severe adverse effects, it is impor­ tant to limit the dose and duration of treatment to what is thought to be clinically useful (Lamont 1993). From our previous work (Holleboom et al. 1993) we had anticipated that the LD schedule would result in lower infusion rates and a smaller total amount of rito- drine than the conventional ID schedule recommended by the manufacturer. While it is dis­ appointing that this did not materialize, there is an explanation for it. Being aware of the potential hazards of ritodrine administration and the fact that side effects are associated nearly as much with changes in infusion rates as with the rates themselves (Caritis et al. 1983 & 1984), clinicians had become more cautious in their application of the convention­ al infusion schedule. This was evidenced by the fact that clinicians tended to observe longer intervals between dose increments than the ID protocol prescribed. While increasing expe­ rience with the new loading dose regimen may have accentuated this tendency, data were not analyzed before completion of the trial and there was no evidence that the incremental regimen was applied less conscientiously at the end than at the beginning of the trial.

Despite the more cautious approach in applying the conventional regimen, the load­ ing dose schedule was still tolerated better, particularly during the initial and most cru­ cial first 12 hours of treatment. On the whole, the incidence of all side effects was greater with the ID than with the LD schedule, but the difference was less pronounced than we had anticipated. We should point out that clinicians and pregnant women were not blind­ ed to the treatment schedule and that only the analysis of data, but not their registration, occurred without knowledge of the treatment group. As anticipated, tocolysis was reached with far fewer dose adjustments when using the LD rather than the ID schedule. This may have a beneficial effect in that each dose adjustment carries a risk of error. This is particularly important when the adjustment calls for an increase in infusion rate and when the clinical staff has relatively little experience with the use of this powerful agent. On the whole, there was a trend for neonatal outcome to be better with the LD than with the ID schedule, but most of the difference is compatible with chance. There was a marked difference in the incidence of periventricular-intraventricular haemorrhage in favour of the LD regimen. This should be interpreted with caution as a difference in this outcome was not a prior hypothesis of the trial. Nevertheless, there could be a plausible mechanism in that virtually all cases were observed in infants born during or shortly after the arrest of ineffective tocolytic treatment. The immature brain is less well protected against acute fluctuations in blood pressure than the brain of the mature infant (Groóme et al. 1992). Van de Bor and Walther (1992) reported that there is only a narrow range of pres­ sure over which cerebral blood flow in preterm infants remains relatively constant. Thus, fluctuations in ritodrine levels to which infants, like their mothers, are exposed may be important. Betamimetic-induced increases in fetal cardiac output (Vetter et al. 1985), parti­ cularly when combined with a redistribution to the upper body as suggested by Petersen et al. (1989), may lead to significant increases in the perfusion pressure to various regions of the brain. While several studies found no significant associations between betamimetic drug treatment and the incidence of periventricular-intraventricular haemorrhage in pre­ term infants (Levene et al. 1982; van de Bor et al. 1987; Laros et al. 1991), others have report­ ed a more than twofold increase in the incidence of periventricular-intraventricular hae­ morrhage in infants whose mothers had been treated with betamimetics (Groóme et al.

78 RANDOMIZED TRIAL OF RITODRINE REGIMENS IN PRETERM LABOUR

1992). The best data available originate from the randomized controlled trials of betami- metic treatment (King et al. 1988; Canadian Preterm Labor Investigators Group 1992). These do not indicate an increased risk of periventricular-intraventricular haemorrhage and the results of the largest trial are more likely to be compatible with a decrease rather than an increase in its incidence (Canadian Preterm Labor Investigators Group 1992). This does not necessarily exclude, though, that our present findings represent a true instead of a chance difference between the two treatment regimens. If this were so, it would consti­ tute a major advantage for the loading dose regimen. As the loading dose scheme is at least equally effective as the incremental dose sche­ dule while needing fewer dose adjustments and being better tolerated in practice, we recommend the loading dose schedule as the preferred and safest of the two approaches to tocolytic treatment with ritodrine in preterm labour.

Acknowledgemen ts

We are grateful to our colleagues at the five participating hospitals in the Netherlands (Leiden University Hospital, Leiden; Laurentius Hospital, Roermond; Bronovo Hospital, The Hague; Maria Hospital, Tilburg; and Utrecht University Hospital, Utrecht) for their collaboration.

79 80 CHAPTER 7

DOUBLE-BLIND EVALUATION OF RITODRINE SUSTAINED RELEASE FOR ORAL MAINTENANCE OF TOCOLYSIS AFTER ACTIVE PRETERM LABOUR

81 Chapter 7 DOUBLE-BLIND EVALUATION OF RITODRINE SUSTAINED RELEASE FOR ORAL MAINTENANCE OF TOCOLYSIS AFTER ACTIVE PRETERM LABOUR

C.A.G. HOLLEBOOM, J.M.W.M. MERKUS, L.W.M. VAN ELFEREN and M.J.N.C. KEIRSE

Department of Obstetrics and Gynaecology, Bronovo Hospital, The Hague, The Nether­ lands C.A.G. HOLLEBOOM Consultant Department of Obstetrics and Gynaecology, St. Radboud Hospital, Catholic University Nijmegen, The Netherlands J.M.W.M. MERKUS Professor Medical Department, Duphar Nederland, Weesp, The Netherlands L.W.M. VAN ELFEREN Scientific Officer Department of Obstetrics and Gynaecology, Flinders Medical Centre, Flinders University Adelaide, Autralia M.J.N.C. KEIRSE Professor

Br. J. Obstet. Gynaecol. 1996; 103: 702-705

Running title: Oral maintenance treatment in preterm labour

ABSTRACT

Objective - To evaluate the effect of ritodrine sustained release capsules for maintaining ute­ rine quiescence after successful treatment of active preterm labour.

Design - Multicentre placebo-controlled trial

Setting - Five teaching hospitals in the Netherlands.

Participants - Women (n = 95) at less than 35 weeks' gestation in whom active preterm labour had been stopped with intravenous ritodrine.

Interventions - Women received either two 40 mg ritodrine sustained release capsules (n = 50) or identical placebo capsules (n = 45) three times a day for 7 days.

Results - The proportion of women who received another course of active treatment was sig­ nificantly smaller with the sustained release than with placebo (1 of 50 versus 11 of 45: ρ - 0.003) as was the number delivering because of preterm labour during treatment (0 of 50 versus 4 of 45: ρ = 0.04). There were no other significant differences between the two groups.

82 Oral maintenance treatment in preterm labour

Conclusion - Maintenance treatment with ritodrine sustained release capsules after arrest of preterm labour reduces the risk of recurrences of preterm labour that necessitate treatment or precipitate delivery.

Introduction

There is some evidence from controlled studies that inhibition of preterm labour with betamimetics is more likely to be effective when intravenous treatment is followed by oral maintenance than when it is not. That evidence is weak, however, and spread across three small studies not all of which used the same betamimetic agent (Creasy et al. 1980; Brown and Tejani 1981; Smit 1983). Among them they only showed fewer relapses and longer relapse free intervals, but no reduction in the incidence of preterm birth (Keirse et al. 1989; Cabrai 1994). These not particularly impressive effects require the frequent intake of a large number of tablets in order to compensate for the low bioavailability and short half-lives of oral betamimetics (Schiff et al. 1993). The use of ritodrine in a sustained release formulation permits the limitation of beta- mimetic intake to three times a day while obtaining plasma levels that parallel the lower range of effective intravenous treatment (Essed et al. 1988) with few side effects (Essed et al. 1988; Witter et al. 1988). We wished to examine whether the use of this sustained release preparation would be sufficiently effective in reducing recurrences of preterm labour to warrant its use in clinical practice.

Participants and methods

A placebo-controlled comparison of ritodrine sustained release capsules for maintaining uterine quiescence after arrest of preterm labour was conducted with ethical approval at five Dutch teaching hospitals. Women recruited for the study were those who had partici­ pated in a randomized comparison of two regimens of intravenous ritodrine administra­ tion, described elsewhere (Holleboom" et al. 1996), and in whom this had resulted in the arrest of active preterm labour. Of the 143 women in whom preterm labour had been stop­ ped with either one of two ritodrine regimens (Holleboom3 et al. 1996), 18 were not eligible because they had received indomethacin (n = 6), had ruptured membranes (n = 2), had experienced severe side effects during intravenous treatment (n = 4), or were beyond 34 weeks of gestation (n = 6). Of the 125 women who were eligible, 30 did not participate in the present study: 16 because they received active treatment without blinding; 8 because of transfer to a non-participating hospital or lack of consent; and 6 for reasons that were not documented. Thus, 95 women participated in the trial; 50 of them had originally received the loading and 45 the incremental dose schedule of intravenous treatment (Holleboom» et al. 1996; Table 1). It had been estimated that with an anticipated >90% success rate of the active treat­ ment a sample of 100 women would have 80% power to detect a 20% difference in the fre­ quency of successful maintenance between the active treatment and placebo (two-tailed α = 0.05). Success was defined as no delivery and no administration of a new course of acti­ ve tocolytic treatment (intravenous tocolysis) during the 7 days of maintenance. At the start of maintenance treatment, all women had been on an intravenous dose of 50 μg/min ritodrine for 12 - 24 hours following successful arrest of contractions. Maintenance consisted of either two 40 mg ritodrine sustained release capsules or two identical placebo capsules three times a day for 7 days supplied in block-randomized,

83 Chapter 7 pharmacy-coded drug boxes. The protocol recommended bedrest for the first 48 hours and hospitalisation for the duration of the 7 days' maintenance treatment. A new episode of intravenous treatment was prescribed with the same regimen that the woman had recei­ ved previously if active labour recurred before 34 weeks' gestation. Maintenance treatment was to be stopped in the event of severe side effects, intrauterine infection, fetal distress, recurrent preterm labour requiring intravenous treatment or leading to delivery, or after 7 days. Other tocolytic agents were not used. The main outcome parameters were administration of another course of intravenous tocolysis and delivery during the 7 days of maintenance treatment. Additional predefined outcomes were: number of deliveries before 35 and 37 weeks and the presence of side effects irrespective of whether or not these prompted arrest of treatment. Statistical analysis was by χ2 test, Fisher exact test for expected numbers below 5, and confidence interval analysis (Gardner and Altman 1989). A two-tailed ρ value <0.05 was considered to be statistically significant.

Table 1 Baseline characteristics of women participating in the oral maintenance trial

Characteristics Ritodrine Placebo no. of women or mean (SD) n=50 n=45

Age (years) 29.0(5.2) 28.7(5.0) 0.80' Duration of pregnancy at 219(14) 219(16) 0.84' trial entry (days)

Multiple pregnane 0.0062 twins 7 triplets 1

Tocolytic index 2.8(0.9) 3.0(1.1) 0.573 (Baumgarten & Grüber 1974)

Bishop score 4.0(1.8) 4.2(1.7) 0.643

Intravenous ritodrine treatment prior to trial entry Treatment schedule 0.594 loading dose 25 25 incremental dose 25 20 Total duration in days 4.1 (3.2) 3.9 (2.2) 0.805 Intravenous treatment until tapering off duration in hours 45 (15) 55 (33) 0.37s dose of ritodrine (mg) 433 (410) 434 (368) 0.865

Statistical tests: ' t test, г Fisher exact,3 Cochran-Mantel-Haenszel, " χ2 test,5 Wilcoxon

84 Oral maintenance treatment in preterm labour

Results

Only 1 (2%) of the women receiving ritodrine sustained release capsules underwent a new intravenous infusion as opposed to 10 (22.2%) of those receiving placebo capsules, a dif­ ference that is highly significant (χ2 = 7.6, ρ = 0.006; Table 2). One woman (after loading dose allocated to placebo) did not comply with maintenance treatment and was given indo- methacin. A further placebo-treated woman had a recurrence of preterm labour deemed to be beyond rescue; she delivered without re-infusion. All but one of the re-infusions occur­ red within the first three days of stopping intravenous treatment and three of the women (all in the placebo group; Table 2) delivered despite re-infusion.

Table 2 Outcome characteristics with the two maintenance treatments

Outcome Ritodrine Placebo Difference (%) and (n = 50) (n = 45) 95% confidence interval

New active treatment 1 11 -22.4 -35.6 to -9.3 intravenous ritodrine 1 10* -20.2 -33.0 to -7.5 indomethacin 0 1 ** -2.2 -6.5 to 2.1

Delivered within 7 days 1 *** 4 -6.9 -16.1 to 2.3 before 35 weeks 2 6 -9.3 -20.7 to 2.0 before 37 weeks 16 13 3.1 -15.4 to 21.6

Discharged from hospital within 5 days 10 8 2.2 -13.5 to 18.0 within 7 days 20 19 -2.2 -22.0 to 17.6 not before delivery 3 7 -9.6 -22.0 to 2.9

Treatment stopped due to side effects 1 0 2.0 -1.9 to 5.9

Side effects Headache 1 0 2.0 -1.9 to 5.9 Hypertension 0 1 -2.2 -6.5 to 2.1 Tremor 2 0 4.0 -1.4 to 9.4 Vomiting 1 0 2.0 -1.9 to 5.9 Neurological problems 0 1 -2.2 -6.5 to 2.1

Fetal and neonatal deaths 1 0 2.0 -1.9 to 5.9

of whom 3 delivered within 7 days and below 34 weeks Caesarean section because of vaginal bleeding in the absence of contractions Lack of compliance with maintenance treatment

85 Chapter 7

There was also a statistically significant difference in the number of women delivering because of recurrent preterm labour during treatment (0 versus 4; Fisher exact, ρ = 0.04), but not in the total number of deliveries during treatment (Table 2). There were no other statistically significant differences between the groups; neither in duration of hospitalisa­ tion, gestational age at delivery or incidence of side effects (Table 2). In only one woman (in the ritodrine group) treatment was stopped because of side effects (headache; Table 2). There was one case of abruption four days after stopping placebo treatment and one death: an unexplained intra-uterine death of a mature infant two months after the end of the trial (ritodrine group) and a further 27 days of open oral ritodrine treatment. Except for this death and one mother who could not be traced after moving to another city, all mothers and infants were well at follow-up in the postneonatal period.

Discussion

Although virtually all controlled trials of betamimetic agents in the treatment of preterm labour have incorporated an episode of maintenance treatment (King et al. 1988; Canadian Preterm Labor Investigators Group 1992), there is divergence of opinion among countries and individual obstetricians on whether maintenance treatment is worthwhile after arrest of active preterm labour (Keirse 1984; Lamont 1994). There are many reasons for this, not the least of which is lack of evidence that such treatment reduces the preterm birth rate (Keirse et al. 1989; Cabrai 1994). Other reasons relate to a wide range of potential, albeit mainly hypothetical effects of prolonged exposure of fetal beta-adrenergic receptors to betamimetic agents (Keirse 1984). Still others reflect concepts, such as down-regulation of beta-adrenergic receptors (Berg et al. 1985; Schneider 1994) that may limit the utility of long-term tocolysis, or beliefs that tocolytic treatments are symptomatic in nature and thence superfluous when symptoms are no longer present. These many persuasions gain a great deal of impetus from the limited bioavailability of betamimetics after oral admini­ stration and the short half-lives which require tablets to be taken at frequent intervals throughout the day and night, if pharmacological credibility is to be sustained (Keirse 1984; Smit et al. 1984; Witter et al. 1988; Schiff et al. 1993). Yet, many clinicians feel some­ thing incongruous in awaking a woman, who is finally asleep after the uterus has been subdued, merely to maintain the status quo so that she can sleep again. Oral preparations of ritodrine have a bioavailability of about 30% (Gandar et al. 1980; Essed et al. 1988) and they must be taken 6 times a day in order to maintain reason­ able plasma levels (Smit et al. 1984). It has been argued that the low efficacy of the medi­ cation is often due to inadequate plasma levels (Schiff et al. 1993). With the sustained re­ lease capsules three doses of 80 mg a day are sufficient to obtain plasma levels that are equivalent to those obtained with an intravenous infusion of 50 μg/min ritodrine without serious side effects (Essed et al. 1987,1988). The fact that only one of 95 women in our study failed to comply with the prescribed maintenance of three doses a day suggests that this treatment is much easier to endure than the usual regimens that require around the clock administration. Our study now clearly demonstrates that sustaining uterine relaxation with this regimen of ritodrine maintenance reduces the likelihood that women will require another course of intravenous treatment. There is now also evidence that this treatment is more likely to delay delivery for at least 7 days than no maintenance treatment. These conclu­ sions gain further credence from the fact that there were significantly more multiple preg­ nancies in the ritodrine than in the placebo arm of the trial. Both effects can be clinically

86 Oral maintenance treatment in preterm labour worthwhile especially when considered in terms of the hazards and maternal discomfort arising from each new course of intravenous betamimetic treatment, as well as the cost of re-admission and hospitalisation of women with recurrent preterm labour.

Acknowledgements

We are grateful to our colleagues at the five participating hospitals in the Netherlands (Leiden University Hospital, Leiden; Laurentius Hospital, Roermond; Bronovo Hospital, The Hague; Maria Hospital, Tilburg; and Utrecht University Hospital, Utrecht) for their collaboration.

87 88 CHAPTER 8

GENERAL DISCUSSION

89 Chapter 8 GENERAL DISCUSSION

CLASSIFICATION OF PRETERM BIRTH

Preterm birth is still the most important cause of neonatal morbidity and mortality despite many medical and social interventions aimed at reducing its frequency or its conse­ quences. Some progress has been made in understanding the aetiology of preterm birth. Instead of seeing preterm birth as a social disease only (a result of poor socio-economic cir­ cumstances, poverty, racial subculture, etc.) it is now considered to be a disorder with a multifactorial background (Creasy 1993). This has resulted in a new aetiological classifica­ tion of preterm birth: a) spontaneous ("idiopathic") preterm labour, b) preterm birth after preterm prelabour rupture of membranes (PPROM) and c) medically indicated ("iatroge­ nic") preterm birth. However, this classification is far from perfect and it certainly does not cover every or even the most important categories of preterm labour and /or birth. When considering strategies to prevent preterm birth it is important to distinguish different sub­ divisions correctly enough to asses whether specific interventions are effective or not. Idiopathic preterm labour implies that there is no external or reasonable cause for this process. Lettieri et al. (1993), however, found an explanation or possible cause in all but 4% of women delivering preterm without prelabour rupture of membranes. Not all of these explanations play a significant role in either the aetiology or the pathophysiology of preterm labour such as it is known today. Yet, they support the view that the notion "idio­ pathic" preterm birth is inappropriate. It is better to name this situation as it is: i.e. preterm birth of unknown cause. This has the advantage that it stimulates rather than stifles the search for potential causes. In addition, "medically indicated" and "iatrogenic" preterm birth are not one and the same category. Within this "medically indicated group" there are women who expe­ rience preterm contractions while having serious pregnancy pathology that contraindica- tes interventions to prolong pregnancy. In this group are also women who may well suffer from similar pathology, but in whom preterm birth is not a spontaneous process and in whom preterm birth is the result of deliberate obstetric intervention to end pregnancy before term. These two entities are clearly different and they can be named unambiguously. It is better to recognize separately preterm labour that is associated with pathology in mother, baby or pregnancy and distinguish it from those births that result from obstetric intervention. Therefore we propose to subdivide preterm on the basis of the cause as follows:

1) preterm birth resulting from spontaneous preterm labour. a) in the absence of significant pathology in mother or baby. b) with significant pathology in mother and/or baby (this often precludes attempts at prolonging the pregnancy or postponing birth).

2) preterm birth initiated by rupture of the membranes before the onset of labour - like uterine contractility. a) in the absence of significant pathology in mother or baby. b) with significant pathology in mother and/or baby (this too will often preclude attempts at prolonging the pregnancy or postponing birth).

90 GENERAL DISCUSSION

3) preterm birth in which the aetiological mechanism is obstetric intervention rather than either spontaneous labour or ruptured membranes.

In addition to the above subdivision it should be realised that preterm at, for instan­ ce, 24 weeks is a different clinical problem from that occurring at, for instance, 36 weeks. This does not mean that the aetiology is different, but the outlook for mother and baby are clearly different. Therefore it is useful to divide preterm births on the basis of the gesta­ tional age at which they occur. Such a subdivision could be:

* mildly preterm: birth between 32 and 36 weeks of gestation

* very preterm: birth before 32 completed weeks of gestation

* extremely preterm: birth before 28 completed weeks of gestation

A sensible use of these classifications may well lead to a better appreciation of what can be gained by the application of various interventions.

PREVENTION OF PRETERM BIRTH AND EARLY DETECTION OF PRETERM LABOUR

The best strategy in dealing with preterm birth is primary prevention. In this respect we should realize that an important risk factor in preterm birth is multiple pregnancy: the mean age at delivery in twins is 37 weeks and in triplets 34 weeks of gestation. Since the introduction of several new methods of assisted reproduction the number of multiple births in general and of high order multiple births in particular is rising (van Duivenboden et al. 1991). The rising number of women using assisted reproduction, howe­ ver, is not the only explanation for the increase in multiple births. In several studies it has been shown that the age of the mother is related to the rate of dizygotic twinning: women of 35-40 years have twice as much chance to deliver di­ zygotic twins as compared to women younger than 25 years.

Primary prevention means therefore:

* Reducing the need for assisted reproduction

* Improving the control of assisted reproductive techniques, especially the use of ovulation inducing agents

* Changing the tendency for postponing pregnancy until a higher age

Furthermore primary prevention can be reached by being more restrictive in inter­ ventions aimed of inducing labour before term or terminating pregnancy otherwise. Also, multifetal pregnancy reduction effectively reduces the risk of early preterm delivery in high-order multiple gestations but is a poor solution to a problem that should occur less frequently after infertility therapy (Berkowitz et al. 1996).

91 Chapter 8

Identification of high risk patients is mandatory to implement individual preventi­ ve measures. Unfortunately there are no adequately discriminative tools to select high risk patients. The presence of fetal fibronectin in cervico-vaginal secretions may give an indi­ cation of activity or damage of the fetal membranes and may be useful in selecting patients at high risk for preterm delivery (Lockwood et al. 1991). However, as a screening test at 24 to 36 weeks of gestation the positive predictive value of fetal fibronectine is only 25% to 30% (Lockwood et al. 1993). This is disappointingly low and not much higher than that of other predictive tests, such as risk scoring systems (Creasy et al. 1980) and ambulatory home uterine activity monitoring (Morrison et al. 1987). Early cervical changes, i.e. shorte­ ning or dilatation, in some cases precede the preterm labour process. Repeat assessment of the cervix may help in detection of these patients, albeit that the positive predictive value is poor (Andersen et al. 1990, Leveno et al. 1986, Buekens et al. 1994). It has been shown that women detected as having bacterial vaginosis in early preg­ nancy have a 5-fold increased risk of preterm birth and late miscarriage (Kurki et al. 1992, Hay et al. 1994). It seems worthwhile to pay more attention to this problem of vaginal bac­ terial colonisation. Infection plays a major role in the causation of preterm labour, especially in prelabour preterm rupture of the membranes (Lamont and Fisk 1993). The diagnostic test for bacterial vaginosis is simple and requires only a wet swab of the vagina (McCoy et al. 1995). Wheter and how antibiotic treatment should be administered for bacterial vagi­ nosis has to be determined. When treatment is indicated it certainly should be started early in pregnancy before inflammation triggers the cytokine cascade. Newer developments in early detection of the preterm labour process are biochemi­ cal markers, such as placental corticotrophin-releasing hormone (Wolfe et al. 1990) and the inflammatory cytokines and prostaglandins that may be involved in precocious cervical maturation. There is still need for adequately controlled research before these tests can be recommended and introduced in general obstetric praxis.

CANDIDATES FOR TOCOLYSIS

The boundary of fetal viability is not clear-cut, but is nowadays estimated to be at 24 weeks of gestation (Copper et al. 1993). After 34 weeks of pregnancy fetal survival exceeds 98%. Before 24 and after 34 weeks of gestation administration of corticosteroids has no demon­ strated effect on fetal outcome (Crowley31995). Betamimetics and prostaglandin synthesis inhibitors may postpone preterm birth for a few days, but often they will not prevent pre­ term birth. Because of these reasons the use of tocolysis before 24 and after 34 weeks of gestation is questionable. Women with preterm labour of unknown cause or with preterm rupture of mem­ branes followed by contractions without signs of maternal or fetal pathology are can­ didates for tocolytic treatment when they are admitted before labour is too far advanced.

CHOICE OF TOCOLYTIC TREATMENT

Instead of the nihilistic view that tocolysis does not prevent preterm birth nor improve infant outcome, consensus is growing that short-term tocolytic benefits are attainable, especially when the time gained is used to realise the best effect: enhancing fetal (lung) maturation and in utero transfer. Do we really want to prevent preterm birth at all costs? In many instances of pre­ term labour that are treated with tocolytics we do not know the cause of preterm labour,

92 GENERAL DISCUSSION but we know that often subclinical infection may play a role. It can be envisaged that, in some instances and especially those with subclinical pathology, tocolysis may worsen the condition of the fetus. Tocolysis should primary be directed at improvement of infant out­ come and not at achieving term pregnancy. The tocolytic agents in current use, betamimetics and prostaglandin synthesis inhi­ bitors, have limited tocolytic effectiveness but they often prolong pregnancy long enough to improve infant outcome by giving corticosteroids and/or arrange antepartum trans­ port. From this point of view they offer what we require from them: a time gain to imple­ ment outcome improving interventions. Unfortunately, they have a wide range of mater­ nal and fetal side effects. New tocolytic drugs, such as the oxytocin antagonist Atosiban and the calcium blocker Nifedipine, seem promising; they may offer equal or better tocolytic effectiveness with possible less side effects. Further randomised trials are needed to eva­ luate their effectiveness and side effects before these drugs can safely be recommended as treatments of choice in preterm labour. Such studies are currently in progress and their results are awaited with interest. Until then, the drugs of first choice in the treatment of preterm labour are betami­ metics, mainly ritodrine, which has been evaluated better than in any other betamimetic agent. Instead of administering ritodrine by the generally recommended incremental intra­ venous dose scheme, it is better to administer ritodrine by a loading dose infusion scheme so as to minimize side effects and reduce the number of dose adjustments. To prevent recurrences of preterm labour with all of their negative effects such as re-admission, re- infusion, etc., it seems worthwhile to give oral ritodrine maintenance after cessation of intravenous ritodrine treatment.

RECOMMENDATIONS FOR FURTHER RESEARCH

Currently available tocolytic treatment is "reactive"; it is an answer to an already started process of preterm labour. The precise mechanism that starts this process of preterm labour is unknown and more basic research is required to obtain a better understanding of it. It can be anticipated that such an understanding may lead to better and more logical ap­ proaches to the prevention of preterm birth and treatment of preterm labour.

93 SUMMARY

The recommended incremental dose regimen for intravenous ritodrine administration in the treatment of preterm labour needs several dose adjustments to achieve uterine toco- lysis and may lead to plasma concentrations of ritodrine above those needed for uterine relaxation. These dose adjustments and ritodrine plasmalevels higher then those needed for tocolysis can cause an increase of unwanted, often more serious, sometimes life threat­ ening (lung edema), ritodrine induced side effects. Oral maintenance with ritodrine plane tablets after arrest of active preterm labour is like­ ly to reduce recurrence of preterm labour or elongate the recurrence free interval. Because of the low bio-availability of ritodrine tablets and short half life time of ritodrine, very fre­ quent tablet intake is obligate (every 4 hours day and night) which reduces its clinical applicability and decreases patients compliance. In contrast with ritodrine plane tablets, stable ritodrine plasma concentrations comparable with a continuous 50 μg/min ritodrine infusion can be obtained with three times daily 2 capsules of 40 mg ritodrine sustained release.

The aim of this thesis is to develop a loading dose infusion model for ritodrine admini­ stration in preterm labour that: 1) avoids doses in excess of what is needed to maintain ute­ rine quiescence after initial arrest of preterm labour, 2) needs a minimum of dose adjust­ ments to reach this effect; 3) to evaluate effectiveness, safety and applicability of this rito­ drine loading dose model in clinical practice, and 4) to evaluate the efficacy and tolerance of oral maintenance with ritodrine sustained release capsules after initial arrest of active preterm labour by intravenous ritodrine treatment.

In chapter 1 a general introduction is given to the problem of preterm birth. Unless many efforts to prevent preterm delivery the incidence of preterm birth has not changed the last decades in developed countries. Improvements in fetal outcome relay mainly on advances in neonatology and perinatal care and little can be attributed to the prevention of preterm birth. The currently available tocolytic drugs are able to postpone preterm delivery by at the least a few days but do not reduce the incidence of preterm birth. Although this seems a disappointing result, the time gained by postponing preterm delivery with a few days is of major importance for a better fetal outcome when it is used for administration of corti- co-steroids, and if necessary, for antepartum transport to a health centre with appropriate facilities for neonatal and perinatal care. New developments in tocolytic drug treatment are discussed. The chapter ends with the outlines and aims of this thesis.

In chapter 2 a review is given about the aetiology of preterm labour and measurements which can be taken to predict or pre- vent its initiation. The incidence of preterm birth is 8-10% in the USA, Africa and the former USSR, around 7-8% in Latin America and between 4 % to 7% in Europe. Yearly this accounts for 13 million preterm births, the majority in developing countries. Not al preterm babies have the same morbidity and mortality risk and gestational age predicts survival best. Because of this, new subdivisions in preterm birth are suitable: mildly preterm (between 32 and 36 weeks), very preterm (between 28 and 32 weeks) and extremely preterm (birth before 28 weeks of gestation). The very and extremely preterm birth group accounts for a quarter of al preterm births but for 75% of al deaths related to preterm delivery.

94 SUMMARY

The aetiology of preterm labour and delivery is multifactorial. Social, economical and medical factors may al contribute to the initiation of preterm labour. To categorise pre­ term birth to its aetiologic background subdivision into spontaneous preterm labour, pre- labour preterm rupture of membranes and medical indicated preterm delivery is proposed in literature. In general, each group accounts for one third of al preterm births. Whereas spontaneous preterm birth implies that there is no apparent reason for the initiation of the labour process it is better to conclude that in spontaneous preterm labour the cause is unknown in most instances. Careful analysis may reveal possible causes in many cases. Spontaneous preterm birth is predominant in low-risk white populations and is associated with young maternal age, low maternal weight, low or high parity, previous abortion, smoking and early pregnancy bleeding. Prelabour preterm rupture of membra­ nes is predominant in lower social class and strongly associated with infection, although this is certainly not the only cause. Bacterial vaginosis and chorio-amnionitis is more fre­ quently diagnosed in this group and also mechanical causes, like trauma, incompetent cer­ vix and multiple gestation. The medical indicated preterm birth group consists of patients with spontaneous preterm labour in whom maternal or fetal pathology contra­ indícate any pregnancy prolonging treatment and of patients in whom the physician indu­ ces preterm birth because of pregnancy pathology. It is associated with older age, low weight, previous stillbirth and al sorts of placental malfunction. The diagnosis threatening preterm birth is hard to make and patients and their attendants mistaken often when relying on early signs of labour like uterine cramps, vaginal discharge and low back pain. Cervical changes and dilatation are clear signs of labour but that is just what we try to prevent. Probably, the patient herself knows best when there is something going wrong and hospitalisation is needed. Prevention of preterm labour starts with identification of those women with in­ creased risk. Unfortunately, to date, there exists no tests, that screen for preterm labour, with high enough sensitivity and positive predictive value to warrant intervention or treatment. Several of these tests are discussed. Promising are the results obtained with the detection of fetal fibronectin in cervico-vaginal secretions but this test needs further evaluation befo­ re its use can be recommended as a screening modality. Early diagnosis and treatment of vaginal infection (bacterial vaginosis) is another promising development in the prevention of preterm labour that needs further assessment. Prophylactic treatment with betamimetics does not reduce the incidence of preterm birth. In contrast, administration of 17ct-hydroxyprogesterone showed some positive pro­ phylactic effect, although the evidence is weak. Cervical cerclage may, in case of true cer­ vical incompetence, reduce preterm birth rate and seems worthy. Treatment of active preterm labour with tocolytic agents, most commonly betami­ metics, can delay preterm delivery with at least 24 to 48 hours but does not prevent pre­ term birth. Whether it is useful to supplement antibiotics to tocolytic treatment is question­ able. In case of prelabour preterm rupture of membranes, administration of antibiotics may prolong the time interval to the onset of contractions.

In chapter 3 a review is given of presently available tocolytic drugs and of new develop­ ments in tocolytic drugs and tocolytic drug treatment. To date, betamimetics, magnesium sulphate and inhibitors of the Prostaglandine synthesis are worldwide the most frequently used drugs to treat preterm labour. They are administered in active treatment (i.e. to stop threatening preterm labour), in maintenance treatment (i.e. to prevent recurrence of preterm uterine contractions after active treatment)

95 and, in prophylactic treatment (i.e. prevention of the initiation of preterm labour in high risk patients). There is apparent evidence of the efficacy of betamimetics and prostaglandin syn­ thesis inhibitors to inhibit preterm uterine contractions and to postpone preterm delivery, although they do not decrease the incidence of preterm birth. On magnesium sulphate there exists no such clear evidence of its efficacy and metaanalysis did not show any bene­ ficial effect on postponing preterm delivery, on the incidence of preterm delivery nor on improvement of fetal outcome. Betamimetics are potent drugs and may induce many side effects, especially in the mother. Continuous administration of betamimetics can induce receptor downregulation and loss of effectiveness. The presently recommended incremental dose scheme for rito- drine administration leads to ritodrine plasma concentrations above those needed for ute­ rine quiescence. New developments in route of and in dose administration to overcome all these latter problems are discussed. Indomethacin, the most widely used prostaglandin synthesis inhibitor, has severe potential fetal side effects and should not be used longer than 48 hours and after 32 weeks of gestation. Sulindac, a drug closely related to indomethacin but with less fetal side effects, seems promising in the treatment of preterm labour but needs further evaluation before it can be recommended. The position of the newer tocolytic agents, the oxytocin antagonist Atosiban and the calcium blocker Nifedipine, is discussed. Until the results of randomised controlled clini­ cal trials, which are in progress now with these drugs, are available, Atosiban and Nifedipine should not be used in routine clinical practice.

In chapter 4 a pilot study of a loading dose infusion scheme for ritodrine administration in preterm labour is presented. This loading dose scheme was based on the ritodrine eli­ mination half-life time (t1/2el) of 2 hours and aimed to prevent ritodrine plasma levels above those needed for tocolysis. The pharmacokinetic background of the loading dose is explain­ ed. In 12 healthy patients, in preterm labour and treated with the loading dose scheme, plasma samples of ritodrine were taken at the moment of tocolysis and during the steady state. These ritodrine plasma concentrations were compared with each other and with expected and calculated plasma concentrations. We found that a ritodrine half life time of 1 hour in stead of 2 hours should be used for development of a loading dose infusion sche­ me. Because this half life time is composed of the effects of distribution and disposition of ritodrine in its different compartments, it is called cumulation half life time (t1/2cum).

In chapter 5 the results of a study with a loading model for ritodrine administration in pre­ term labour based on the ritodrine cumulation half life time (t1/2ciim) are presented. As soon as uterine quiescence was achieved the loading dose was reduced to an infusion rate that should stabilize ritodrine plasma concentration. The decrease in infusion rate was cal­ culated on the basis of the interval between start of treatment and tocolysis. Several blood samples were taken at the moment of tocolysis and in the steady state period to determi­ ne ritodrine plasma concentrations which concentrations were compared with each other and with calculated anticipated ritodrine levels. Overall, steady state ritodrine levels were nearly identical to those at the time of tocolysis. The correlation between measured and calculated expected steady state ritodrine concentrations was high (y = 0.97x - 1.6; r = 0.91;

ρ < 0.001). The ritodrine cumulation half Ufe time (t1/2cum) of 50 min was confirmed in this study.

96 SUMMARY

Patients tolerate the loading dose well. Very few dose adjustments were required to reach the maintenance infusion rate, which rate was rather low as was the quantity of ritodrine used in these patients.

In chapter 6 a multicentre randomised trial comparing ritodrine administration in preterm labour by loading dose and incremental dose is presented. Women (n = 203), in preterm labour at less than 34 weeks of gestation, received either a loading dose ritodrine infusion followed, as soon as tocolysis was reached, by a decrease in infusion rate or the conven­ tional incremental schedule of increasing doses until uterine quiescence was achieved. Overall the differences between the two dose regimen were unexpectedly small. The total amount of ritodrine used until the start of tapering off did not differ between groups. The mean infusion rates at 12, 24 and 48 hours after start of treatment was similar as was the duration of intravenous treatment until the start of maintenance. Probably this is a re­ flexion of the cautious application of the incremental dose regimen, less frequent and with longer time intervals than the original recommended incremental schedule, by patient's clinicians being aware of the potential hazards of ritodrine administration. Frequency of successful tocolysis (71 %) and duration of treatment (55h) were similar in both groups, but the loading dose schedule was better tolerated with fewer adverse events. Also the num­ ber of dose adjustments was smaller than in the incremental dose group (P < 0.001). Because there appears to be no disadvantages to the loading dose schedule neither in terms of tocolytic power nor in terms of perinatal outcome while side effects were less frequent as was the number of dose adjustments makes that the loading dose regimen should be preferred above the incremental schedule.

In chapter 7 the results of a multicentre double blind evaluation of ritodrine sustained re­ lease for oral maintenance of tocolysis after arrest of active preterm labour are presented. Women (n = 95) at less than 35 weeks' of gestation, in whom active preterm labour had been stopped with intravenous ritodrine, received either two 40 mg ritodrine sustained release capsules (n = 50) or identical placebo capsules (n = 45) three times a day for 7 days. With the ritodrine sustained release capsules the number of women who received another course of intravenous ritodrine treatment was significantly smaller than with placebo (1 of 50 versus 11 of 45; Ρ = 0.003). In addition, the number of women delivering because of recurrent preterm labour was significant smaller with sustained release ritodrine capsules than with placebo (0 of 50 versus 4 of 45; Ρ = 0.04). We concluded that maintenance treatment with ritodrine sustained release after arrest of preterm labour reduces the risk of recurrence of preterm labour that necessitate another course of intravenous treatment or precipitate delivery.

The general discussion in chapter 8 contains a reflection of the results obtained by litera­ ture study and ritodrine trials described in chapter 1 to 7. A new classification of preterm birth on the basis of the cause and a classification on the basis of the gestational age are proposed. Methods for primary prevention of preterm birth are discussed. Also selection criteria of candidates for tocolysis are given. The drugs of first choice in the treatment of preterm labour are betamimetics, main­ ly ritodrine. When administered, beta-mimetics should be given by an intravenous loading dose schedule. It is worthwhile to give oral ritodrine maintenance after cessation of intra­ venous ritodrine treatment.

97 SAMENVATTING

Vroeggeboorte is de belangrijkste oorzaak van perinatale mortaliteit en morbiditeit. Ondanks maatregelen ter preventie en behandeling van vroeggeboorte is de incidentie ervan de laatste decennia niet gedaald. Behandeling van dreigende vroeggeboorte bestaat hoofdzakelijk uit weeënremming. Van de weeënremmende middelen worden, wereldwijd, betamimetica (meestal ritodrine) het meest toegepast. Toepassing van het in de bijsluiter aanbevolen oplopende doseringsschema voor de intraveneuze toediening van ritodrine by dreigende vroeggeboorte leidt tot meerdere dosisaanpassingen alvorens weeënactiviteit is verdwenen en kan tot hogere ritodrine plas­ ma concentraties leiden dan voor deze weeënremming noodzakelijk is. Zowel de dosis­ aanpassingen als de ritodrine overdosering kunnen ongewenste, vaak ernstige, soms zelfs levensbedreigende (longoedeem) bijwerkingen veroorzaken. De vele momenten van dosisaanpassingen op zichzelf zijn een mogeUjke bron van fouten. Onderhoudsbehandeling met ritodrine oraal, na geslaagde remming van aanvanke­ lijk dreigende vroeggeboorte d.m.v. intraveneuze ritodrine toediening, vermindert moge­ lijk de kans op een recidief van dreigende vroeggeboorte. Bovendien kan de periode tot hernieuwde weeënactiviteit worden verlengd. Door de lage biologische beschikbaarheid van ritodrine na orale toediening en de korte halfwaarde tijd van ritodrine (t1/2cl =2 uur), is zeer frequente orale toediening noodzakelijk (iedere 4 uur dag en nacht) hetgeen zowel de klinische toepasbaarheid vermindert als de therapietrouw verlaagt. Door middel van toe­ diening van ritodrine in de vorm van capsules met vertraagde afgifte kunnen stabiele ritodrine plasma concentraties worden bereikt welke gelijk zijn aan concentraties verkre­ gen met een continue ritodrine infuus van 50 μg/min.

Het doel van de in deze thesis beschreven studies is: A) het ontwikkelen van een ritodrine doserings schema voor toepassing bij dreigende vroeggeboorte dat 1) overdosering voor­ komt en 2) minimale dosisaanpassingen behoeft; B) het evalueren van de veiligheid, effec­ tiviteit en toepasbaarheid van een dergelijk doseringsschema in de praktijk en C) het bestuderen van de effectiviteit van en tolerantie voor ritodrine vertraagde afgifte capsules wanneer deze gegeven worden als onderhoudsbehandeling na aanvankelijke intraveneu­ ze toediening van ritodrine ter behandeling van dreigende vroeggeboorte.

Een algemene introductie van het probleem vroeggeboorte wordt gegeven in hoofdstuk 1. De incidentie van vroeggeboorte is in de westerse wereld de laatste decennia niet gedaald. De betere resultaten verkregen met betrekking tot de overleving en kwaliteit van leven van prematuren moeten hoofdzakelijk worden toegeschreven aan ontwikkelingen in perinata­ le i.h.b. de neonatale zorg en berusten slechts voor een gering deel op de preventie van vroeggeboorte. De hedendaagse beschikbare weeënremmende middelen kunnen de par­ tus bij dreigende vroeggeboorte slechts met enkele dagen uitstellen maar verlagen de inci­ dentie van vroeggeboorte daardoor niet wezenlijk. Hoewel dit een teleurstellend resultaat lijkt is de tijdwinst, verkregen door uitstel van vroeggeboorte met enkele dagen, van groot belang om tot een betere foetale prognose te komen. Deze tijdwinst maakt het mogelijk om corticosteroiden toe te dienen die de foetale (long) rijping versnellen en, indien noodzake­ lijk, antepartum transport te regelen naar een centrum met adequate perinatologische en neonatologische opvang mogelijkheden, interventies die bewezen hebben de foetale mor­ taliteit en morbiditeit te verminderen.

98 SAMENVATTING

Nieuwe ontwikkelingen in tocolytische behandeling worden kort besproken. Als laatste wordt de strekking en de opzet van het onderzoek besproken en de doelstelling uit­ gewerkt.

In hoofdstuk 2 worden de incidentie, aethiologie en diagnose van vroeggeboorte en de daarmee samenhangende mogelijkheden ter preventie en voorspelling ervan in een litera­ tuur overzicht gepresenteerd. De incidentie van vroeggeboorte is 8-10% in de USA, Afrika en de voormalige USSR, ongeveer 7-8% in Latijns Amerika en tussen 4% en 7% in Europa. Wereldwijd betreft het 13 miljoen vroeggeboorten per jaar, het leeuwendeel in de derde wereld. Niet alle (te) vroeggeborenen hebben dezelfde morbiditeit en mortaliteit. De zwan­ gerschapsduur is het meest bepalend voor de kans op overleving en de kans op handicap bij overleven. Om deze reden lijkt een indeling van vroeggeboorte zinvol: vroeggeboorte (geboorte < 37 weken zwangerschapsduur), matige vroeggeboorte (tussen 32 en 36 weken), erge vroeggeboorte (tussen 28 en 32 weken) en extreme vroeggeboorte (geboorte voor 28 weken zwangerschapsduur). De groep erge en extreme vroeggeboorte vormt een kwart van alle vroeggeboorten doch is verantwoordelijk voor driekwart van alle met vroeggeboorte gerelateerde sterfte. De oorzaak van (dreigende) vroeggeboorte is multifactorieel. Zowel sociale, econo­ mische als medische factoren dragen bij aan het ontstaan van (dreigende) vroeggeboorte. In de literatuur wordt vroeggeboorte, ingedeeld naar aethiologie, als volgt gepresenteerd: spontane vroeggeboorte, vroeggeboorte door voortijdig breken van de vliezen en medisch geïndiceerde vroeggeboorte. In het algemeen draagt iedere groep afzonderlijk bij aan een derde van alle vroeggeboorten. De diagnose spontane vroeggeboorte impliceert dat er geen duidelijke verklaring is voor het in gang komen van de baring. Zorgvuldige analyse kan in veel gevallen alsnog een mogelijke oorzaak aan het licht brengen. Spontane vroegeboorte komt voornamelijk voor in de laag risico blanke populatie, en is geassocieerd met jonge maternale leeftijd, laag maternaal lichaamsgewicht, lage en hoge pariteit, eerdere spontane abortus danwei abor­ tus provocatus, roken en bloeding in het eerste trimester. Vroegtijdig breken van de vlie­ zen wordt voornamelijk gezien in lagere sociale klasse en is sterk geassocieerd met infec­ ties zoals bacteriële vaginosis en chorio-amnionitis, doch ook mechanische oorzaken als trauma, incompetente cervix, en meerlingzwangerschap worden hierbij vaker gezien. De medisch geïndiceerde vroeggeboorte groep bestaat uit patiënten met dusdanige zwan- gerschaps pathologie dat de behandelaar het beëindigen van de zwangerschap noodzake­ lijk acht. Hogere maternale leeftijd, een laag maternaal gewicht, eerdere doodgeboorte en placenta insufficiëntie worden met deze groep geassocieerd. De diagnose dreigende vroeggeboorte is zeer moeilijk te stellen. Patiënten en behan­ delaars weten niet goed wanneer hard worden van de uterus, buikpijn,vaginale afschei­ ding en lage rugpijn tekenen zijn van dreigende vroeggeboorte. Veranderingen in de baar- moederhals zoals verweking, verstrijking en ontsluiting zijn onmiskenbare tekenen van het in gang zijn van de baring doch dat willen we juist voorkomen. In de regel blijken de patiënten zelf het beste aan te kunnen geven wanneer er iets niet in orde is en behandeling of ziekenhuis opname noodzakelijk is. Preventie van vroeggeboorte begint bij identificatie van vrouwen met een verhoogd risico op vroeggeboorte. Helaas bestaan er tot heden geen screenings testen met een dus­ danig hoge sensitiviteit en specificiteit dat daarmee vrouwen met verhoogd risico op vroeggeboorte kunnen worden opgespoord. Interventie op basis van deze testen is dan

99 ook niet gerechtvaardigd. Veelbelovend is de bepaling van foetaal fibronectine in cervico- vaginale afscheiding. De test behoeft nog verdere evaluatie voordat deze kan worden aan­ bevolen als algemene screening. Een andere mogelijk gunstige aanpak ter preventie van vroeggeboorte lijkt de vroegdiagnose en behandeling van vaginale infecties (i.h.b. bacte- riële vaginosis). De waarde hiervan dient in nader onderzoek te worden aangetoond. Het profylactisch voorschrijven van betamimetica aan risico patiënten verlaagt de incidentie van vroeggeboorte niet. Daarentegen lijkt het toedienen van 17cc-hydroxypro- gesteron wel zinvol, hoewel het bewijs hiervan niet erg sterk is. Bij bewezen cervix insuf- ficiëntie verlaagt cerclage de kans op vroeggeboorte. Behandeling van dreigende vroeggeboorte met sommige weeënremmende midde­ len kan de baring op zijn minst 24 tot 48 uur uitstellen doch voorkomt vroeggeboorte niet. Het is discutabel of het toevoegen van antibiotica aan tocolytische behandeling zinvol is. Bij vroegtijdig gebroken vliezen kan het toedienen van antibiotica het tijdsinterval tussen het breken van de vliezen en het begin van weeënactiviteit verlengen.

In hoofdstuk 3 wordt een literatuur overzicht gegeven van de huidige beschikbare weeën­ remmende middelen en van nieuwe ontwikkelingen op het gebied van weeënremmende behandeling. Wereldwijd worden momenteel 1) betamimetica, 2) Prostaglandine synthese rem­ mers en 3) magnesiumsulfaat, het meest toegepast in de behandeling van dreigende vroeg­ geboorte. Deze middelen worden toegepast bij de actieve behandeling (weeënactiviteit te remmen bij dreigende vroeggeboorte), bij onderhouds behandeling (heroptreden van con­ tracties na geslaagde actieve behandeling voorkomen) en als profylactische behandeling (het ontstaan van vroegtijdige contracties voorkomen in een hoog risico populatie). De effectiviteit van betamimetica en Prostaglandine synthese remmers met betrek­ king tot weeënremming en uitstel van de baring is aangetoond doch het staat vast dat zij vroeggeboorte niet kunnen voorkomen. De effectiviteit van magnesium sulfaat, daarente­ gen, is niet bewezen en een metaanalyse van de resultaten van studies met magnesium­ sulfaat toont geen effect op uitstel van de baring, op verlaging van de incidentie van vroeg­ geboorte noch op verbetering van de foetale morbiditeit en mortaliteit. De zeer krachtige multipotente betamimetica kunnen vele (ongewenste) bijwerkin­ gen veroorzaken, vooral in de moeder. Daarnaast kan continue toediening van betamime­ tica leiden tot receptor down-regulatie en verlies van effectiviteit. Toediening van ritodri- ne middels het aanbevolen oplopende doseringsschema geeft kans op hogere ritodrine plasma concentraties dan nodig is voor weeënremming. Besproken worden nieuwe ont­ wikkelingen in dosering en wijze van toediening van betamimetica om deze genoemde problemen te voorkomen. De meest gebruikte Prostaglandine synthese remmer, indomethacine, kan zeer ern­ stige foetale bijwerkingen veroorzaken en moet om deze reden niet langer dan 48 uur ach­ tereen en niet na de 32sle zwangerschaps week worden toegediend. Veelbelovend is Sulin- dac, nauw verwant aan indomethacine maar met minder foetale bijwerkingen. Nadere evaluatie van effectiviteit en van mogelijk optredende ongewenste bijwerkingen is nodig alvorens Sulindac kan worden aanbevolen ter behandeling van dreigende vroeggeboorte. De nieuwe tocolytica Atosiban (Oxytocine antagonist) en Nifedipine (calcium blok­ ker) worden besproken. Zolang de resultaten van gerandomiseerd gecontroleerd onder­ zoek met deze middelen niet beschikbaar zijn dienen Atosiban en Nifedipine niet in de dagelijkse praktijk te worden gebruikt.

100 SAMENVATTING

De resultaten van een oplaad doseringsschema voor de toediening van ritodrine bij dreigende vroeggeboorte, gebaseerd op de eliminatie halfwaarde tijd (t1/M) van 2 uur, wor­ den gepresenteerd in een pilot studie in hoofdstuk 4. Het oplaad doseringsschema is ont­ worpen om te voorkomen dat ritodrine plasma concentraties hoger worden dan nodig is voor weeënremming. De pharmacokinetische principes van dit oplaadschema worden uit­ een gezet. Bij 12 gezonde vrouwen met dreigende vroeggeboorte werden ritodrine plasma con­ centraties gemeten op het moment dat weeënremming werd bereikt en gedurende de onderhouds fase. Deze ritodrine concentraties werden met elkaar en met verwachte en berekende concentraties vergeleken. Hieruit kon worden berekend dat in plaats van de eli­ minatie halfwaarde tijd van 2 uur een half waarde tijd van 1 uur moest worden gebruikt tij­ dens de fase van opladen. Deze halfwaard e tijd van 1 uur, samengesteld uit de effecten van distributie en eliminatie van ritodrine, wordt door ons cumulatie halfwaarde tijd genoemd

\l\/2cum)·

In hoofdstuk 5 worden de resultaten van een oplaad doseringsschema voor ritodrine toe­ diening bij dreigende vroeggeboorte gebaseerd op de ritodrine cumulatie halfwaarde tijd (ti/imm) gepresenteerd in een studie met 31 patiënten. Direct nadat weeënremming was bereikt werd de oplaad dosis verlaagd naar een infusie snelheid die de dan aanwezige ritodrine plasma concentratie moest stabiliseren. De mate waarin de infusie snelheid moest worden verlaagd werd berekend aan de hand van het tijdsinterval tussen start van de behandeling en het bereiken van weeënremming. Meerdere ritodrine plasma concen­ traties, gemeten op het moment van tocolyse en in de onderhouds fase, werden met elkaar en met verwachte berekende concentraties vergeleken. In grote lijnen waren de ritodrine plasma spiegels gemeten in de onderhouds fase vrijwel gelijk aan die op het moment van het bereiken van weeënremming. De correlatie tussen gemeten en berekende ritodrine plasma concentraties was hoog (y = 0.97x -1.6; r = 0.91; ρ < 0.001). De ritodrine cumulatie halfwaarde tijd (t1/2cum) van 1 uur werd bevestigd in deze studie. Patiënten verdroegen de oplaad dosis goed. Er waren zeer weinig dosis aanpassin­ gen nodig om de onderhouds infusie snelheid te bereiken. Bovendien was deze snelheid en daarmede de bereikte concentratie nogal laag evenals de totale hoeveelheid benodigde ritodrine.

In hoofdstuk 6 wordt een gerandomiseerd onderzoek beschreven dat het ritodrine oplaad doseringsschema vergelijkt met het oplopende doseringsschema bij 203 vrouwen met dreigende vroeggeboorte en een zwangerschaps duur van % 34 weken. In grote lijnen waren de verschillen tussen de beide doseringswijzen klein. Er bestond tussen beide sche­ mata geen verschil in de totale hoeveelheid gebruikte ritodrine tot het moment dat de behandeling werd uitgeslopen. De gemiddelde ritodrine infuus snelheid 12, 24 en 48 uur na aanvang van de behandeling was gelijk evenals de duur van de intraveneuze behande­ ling totdat werd uitgeslopen. Vermoedelijk is dit een gevolg van een door behandelaars voorzichtige manier van toepassen van het oplopende schema (aanpassingen vonden min­ der frequent en met grotere tussenpozen plaats dan het oorspronkelijke oplopende sche­ ma voorschrijft) ingegeven door het besef van de risico's van ritodrine toediening. De frequentie waarin tocolyse succesvol was en de duur van de behandeling was gelijk in beide groepen. Het oplaad schema werd beter verdragen en leidde tot een lager aantal ernstige bijwerkingen. Ook het aantal dosisaanpassingen was veel lager dan met het oplopende schema (P <0.001).

101 Daar er geen duidelijke nadelen kleven aan het oplaad schema, terwijl het aantal bij­ werkingen en het aantal dosis aanpassingen minder zijn verdient het oplaad schema, uit oogpunt van veiligheid, de voorkeur boven het oplopende schema.

In hoofdstuk 7 worden de resultaten van een gerandomiseerd dubbelblind onderzoek van orale onderhoudsbehandeling met ritodrine vertraagde afgifte capsules, in aansluiting aan intraveneuze behandeling van dreigende vroeggeboorte met ritodrine, gepresenteerd. Totaal 95 vrouwen met een zwangerschaps duur van minder dan 35 weken kregen, na suc­ cesvolle intraveneuze tocolyse, gedurende 7 dagen hetzij drie maal daags twee ritodrine vertraagde afgifte capsules van 40 mg (n = 50) hetzij identieke placebo capsules (n = 45). Het aantal hernieuwde intraveneuze ritodrine behandelingen was bij vrouwen die ritodri­ ne vertraagde afgifte capsules gebruikten significant lager dan bij de placebo gebruiksters (1 van de 50 versus 11 van de 45). Daarnaast, gedurende de studie periode van een week na het beëindigen van de intraveneuze behandeling, was het aantal vroeggeboorten signi­ ficant geringer bij vrouwen die ritodrine vertraagde afgifte gebruikten (0 van de 50 versus 4 van de 45; Ρ = 0.04). Onderhoudsbehandeling met ritodrine vertraagde afgifte, na aanvankelijke succes­ volle intraveneuze behandeling van dreigende vroeggeboorte met ritodrine, verlaagt de kans op recidief van uterus contracties die een nieuwe intraveneuze behandeling noodza­ kelijk maken of tot vroeggeboorte aanleiding geeft.

Hoofdstuk 8 geeft een beschouwing van de resultaten van literatuur onderzoek en rito­ drine studies zoals in voor-afgaande hoofdstukken 1-7 beschreven. Een nieuwe indeling van vroeggeboorte naar oorzaak en een indeling van vroegge­ boorte naar zwangerschapsduur worden voor-gesteld. Maatregelen ter primaire preventie van vroeggeboorte worden besproken. Tevens worden selectie criteria van candidaten voor weeënremming bij dreigende vroeggeboorte gegeven. Vooralsnog zijn betamimetica, met name ritodrine, de mid-delen van eerste keus bij de behandeling van dreigende vroeg-geboorte maar dan toegedient middels een intrave­ neus oplaad doseringsschema. Het verdient aanbeveling om een orale onderhouds behan­ deling te starten met ritodrine vertraagde afgifte capsules na het stoppen van intraveneu­ ze ritodrine behandeling.

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128 APPENDIX

APPENDIX

Appendix 1

Explanation of the use of an one compartment model instead of a multi compartment model to calculate the pharmacokinetic parameters of ritodrine when given by a conti­ nuous intravenous infusion to pregnant women.

The pharmacokinetics of ritodrine can be best described by a multi-compartment model (Gandar et al. 1980). After intravenous administration, ritodrine is distributed in the cen­ tral compartment and from this central compartment disposed to the peripheral compart­ ment and, in pregnant women, also to the fetal compartment (Gross et al. 1985). Using an one-compartment model for describing the pharmacokinetics of ritodrine is therefor a sim­ plification of the true pharmacokinetics of this drug (Caritis et al. 1983,1990, Gandar et al. 1980), but allows a pragmatical approach to develop a loading dose infusion model for ritodrine administration (Holleboom et al. 1987,1993). In case of a two-compartment model the formula for the plasma concentration of a drug given by continuous infusion is:

C, = C, (1 - e^6*3"") + О* (1 - e°™"a) (1)

distribution disposition

because e41693 = 2'1 formula (1) can be written:

C, = C», (1 - 2-"") + C^ (l-2"c) (2) R

In steady state : Cx = and the elimination rate VK,

constant Kg relates to the drug half-life time (t1/2)

0.693 according to the equation K, = and in the two compartment model (formula): im

R t, R t2 C, = 1.44 and CU = 1.44

V, V2

In these equations: C, = ritodrine concentration at time t Gu, = contribution to steady state concentration due to distribution C^ = contribution to steady state concentration due to disposition t, = distribution half life t2 = disposition half life V, = volume of central compartment

V2 = apparent volume of distribution R = infusion rate

129 In the two compartment model the ritodrine plasma concentration is depended on four pharmacokinetic parameters of ritodrine (t„ t^ V, and V2), specific for each patient, and with major inter-individual variation (Caritis et al. 1990). In the study of Caritis et al. (1990) these pharmacokinetic parameters were calculated in 13 pregnant women with the follow­ ing results:

Pharmacokinetic parameter mean+SD range max/min ratio

Distribution half life (min) 5.9 + 6.0 1.3 - 21.7 16.7 χ Disposition half life (min) 156 ± 51 79 - 224 2.8 χ

Volume central compartment 34.8 ± 31.4 5.4 - 124.7 23.0 χ

Apparent volume of distribution (1) 440 + 224 121 - 926 7.6 χ

This study confirms our assumption that large inter-individual variations in the pharma­ cokinetic parameters of ritodrine (variations between individuals up to 23 x) make it hazardous, if not impossible, to develop a practical loading dose infusion scheme based on the two compartment model.

Any individual approach, using a two compartment model, would need measure­ ments of plasma concentrations of ritodrine in each patient to calculate the four different parameters, which is not feasible in clinical practice. The more pragmatic approach, using a one compartment model, combines distribution and disposition into just one parameter; the cumulation half life time (t1/2cum). The plasma concentration of ritodrine, when given by continuous intravenous infusion in an one compartment model, can be calculated from the equation:

C, = Q, (1 - 2-,/^cum)

By means of this formula a loading dose infusion scheme based on only one parameter (Ρ*™™) can be calculated (Holleboom et al. 1993).

130 APPENDIX

Appendix 2

Ritodrine preparation for intravenous administration:

One 5 ml ampoule of ritodrine (50 mg) is added to 45 ml of 5% glucose resulting in a ri­ todrine concentration of 1 mg/ml = 1000 mcg/ml.

Consequently:

3ml/h 50 μg/min 6ml/h 100 μg/min 9ml/h 150 μg/min 12ml/h 200 μg/min 15ml/h 250 μg/min 18ml/h 300 μg/min 21ml/h 350 μg/min 24ml/h 400 μg/min 27ml/h 450 μg/min 30ml/h 500 μg/min 33ml/h 550 μg/min 36ml/h 600 μg/min

131 Appendix 3

Ritodrine Loading Dose Schedule (LDS)

Loading dose 200 μg/min ritodrine Tocolysis after Maintenance dose 0-30 min 50 μg/min 31-60 min 100 μg/min 61-90 min 150 μg/min 91-120 min maintain at 200 μg/min

If after two hours uterine contractions had not ceased, the loading dose was increased to 400 μg/min.

Loading dose 400 μg/min ritodrine Tocolysis after Maintenance dose 0-30 min 250 μg/min 31-60 min 300 μg/min 61-90 min 350 μg/min 91-120 min maintain at 400 μg/min

If two hours later uterine contractions had not ceased, the loading dose was increased to 600 μg/min.

Loading dose 600 μg/min ritodrine Tocolysis after Maintenance dose 0-30 min 450 μg/mm 31-60 min 500 μg/mm 61-90 min 550 μg/min 91-120 min maintain at 600 μg/min

A dose of 600 μg/min ritodrine should not be exceeded.

Ritodrine intravenous withdrawal schedule

ritodrine maintenance dose to after 12-24 hours after 12-24 hours during 24-48 hours

50 μg/min infusion stopped - -

100-200 μg/min 50 μg/min infusion stopped -

250-400 μg/min 100 μg/min 50 μg/min infusion stopped

450-600 μg/min 150 μg/min 50 μg/min infusion stopped

132 DANKWOORD DANKWOORD

In 1983 begon in het Maria ziekenhuis te Tilburg de eerste ritodrine studie, later gevolgd door een studie in het Maria ziekenhuis en Elisabeth ziekenhuis te Tilburg en uiteindelijk de studie in 6 ziekenhuizen waaronder het Maria ziekenhuis en Elisabeth ziekenhuis te Tilburg, St. Laurentius ziekenhuis te Roermond, Academisch ziekenhuis te Utrecht, Academisch ziekenhuis te Leiden en het Bronovo ziekenhuis te Den Haag. Wanneer een studie in zoveel centra wordt verricht en daarbij zowel de afdelingen verloskamers en ver­ loskunde alsmede de afdeling neonatologie betrokken is, is elk dankwoord onvolledig. Alle patiënten, verpleegkundigen, co-assistenten, arts-assistenten, verloskundigen, gynae­ cologen, kinderartsen, analisten, klinisch chemici, secretaressen, apothekers, bibliotheca­ rissen en alle anderen die ik vergeten ben wil ik zeer hartelijk danken voor hun medewer­ king zonder welke dit proefschrift nooit tot stand was gekomen. Uiteraard zijn een aantal personen zeer nauw betrokken geweest, beter gezegd onmisbaar, bij het opzetten, uitvoeren en uitwerken van de verschillende studies die uiteindelijk tot dit proefschrift hebben geleid.

Prof. dr. J.M.W.M. Merkus, beste Hans, wat in 1983 onder jouw hoede is gestart wordt ook door jou weer afgerond. Een beter voorbeeld van begeleiding, planning, stimulatie en vol­ harding had je me niet kunnen geven. En passant hielp je mijn dochter ter wereld, wat wil een promovendus nog meer!

Prof. dr. M.J.N.C. Keirse, beste Mare, ons contact dateert uit mijn Leidse studietijd, gevolgd door samenwerking in de eie. cursorisch onderwijs en later de cluster Leiden. Jouw analy­ tisch denken, introductie in klinisch onderzoek, het vinden van praktische oplossingen, redactionele kwaliteiten, onvermoeibare motivatie, humor en lessen in koffie en nicotine hebben zeer veel indruk op me gemaakt.

Drs. L.W.M. van Elferen, beste Leo, jarenlang heb je de ritodrine studies begeleid en heb je mij ingewerkt in de basale principes van pharmakokinetiek en statistiek. Rust, geduld, continuïteit en het minitieus verwerken van alle data, daarvoor ben ik je heel dankbaar.

Mijn beide opleiders dr. H.C.L.V. Koek, beste Hans, en Prof. dr. A.A. Haspels wil ik dan­ ken voor de mogelijkheid die mij geboden is om gynaecoloog te worden.

De lokale coördinatoren in de diverse studie centra, Carla van Oppen, Martin Bergman, Sjarlotte Kooy en Paul Reuwer ben ik veel dank verschuldigd.

Mijn collega's in het Bronovo ziekenhuis, Robert, Piet-Hein en Maddy, ook jullie steun was onontbeerlijk en nogal eens hebben jullie de mijne moeten missen. Dank aan Nicolette van Gemund voor het waarnemen van mijn polikliniek en aan Frank- Willem Jansen voor OK waarneming tijdens mijn "schrijfperiode".

Mijn lieve Annemieke, Sophie en Jules, jullie gaven mij de basis waardoor alles mogelijk werd. Beter had niet gekund!

133 CURRICULUM VITAE

Caspar A.G. Holleboom werd op 30 april 1955 geboren te Tand-Jong Morawa, Lubuk Pakan, Sumatra, Indonesië waar zijn ouders destijds woonden en werkten. In 1972 behaal­ de hij het diploma HBS-B aan het Chrysostomos Lyceum te Boxmeer. Na te zijn uitgeloot voor de studie Geneeskunde volgde hij in 1972 het brugjaar Welzijnszorg aan de Erasmus Universiteit te Rotterdam (hoofd: Prof. Dr. M. de Vries). In 1973 startte hij de studie Geneeskunde aan de Rijksuniversiteit te Leiden alwaar in januari 1980 het artsexamen werd behaald. Het derde jaars keuze practicum tijdens deze studie werd doorgebracht in El-Kef, Tunesië alwaar de vele verloskundige ervaringen het idee deden rijpen om gynae­ coloog te worden (WHO project, chef d'equipe Dr. P.J.C, van der Straaten). Gedurende enkele maanden was hij in 1980 AGNIO aan het Anatomisch Pathologisch Laboratorium van het Academisch Ziekenhuis te Leiden (hoofd: Prof. Dr. Th. G. van Rijssel). Ingaande november 1980 werd de militaire dienstplicht vervult. Als dienst­ plichtig militair arts werkte hij van december 1980 tot januari 1982 op de afdeling Gynaecologie & Obstetrie van het Militair Hospitaal Dr. A. Mathijsen te Utrecht (Dr. Ph. Stoutenbeek en mevr. E.C.G. van Seumeren). April 1982 werd de opleiding Verloskunde & Gynaecologie aangevangen in het Maria Ziekenhuis te Tilburg (opleider: Dr. H.C.L.V. Koek). In de Tilburgse periode werd gestart met de onderzoeken die de basis vormen van dit proefschrift. Vanaf april 1986 werd de opleiding tot vrouwenarts voortgezet in het Academisch Ziekenhuis te Utrecht (opleider: Prof. Dr. A.A. Haspels). Op 1 mei 1987 volgde registratie als gynaecoloog in het nederlandse specialisten register. In oktober 1987 is hij toegetreden tot de maatschap gynaecologie (in associatie met Dr. R.A. Verwey, P.H. Kolkman en mevr. M.J.G.H. Smeets) in het Ziekenhuis Bronovo te Den Haag alwaar hij sedertdien met veel plezier werkzaam is. Cas is in 1983 gehuwd met Annemieke van Rosmalen en vader van Sophie en Jules.

134

STELLINGEN

STELLINGEN BEHORENDE BIJ HET PROEFSCHRIFT "PHARMACOLOGICAL INTERVENTION IN PRETERM LABOUR" DOOR CAS HOLLEBOOM

1. De cumulatie halfwaarde tijd van ritodrine (t1/2cum) is 50±20 minuten. (Dit proefschrift)

2. Met behulp van een intraveneus oplaaddoseringsschema voor ritodrine, gebaseerd op de ritodrine cumulatie halfwaarde tijd, worden ritodrine plasmaconcentraties hoger dan nodig voor tocolyse vermeden. (Dit proefschrift)

3. Het oplaaddoseringsschema voor ritodrine verdient de voorkeur boven het klassieke oplopende doseringsschema aangezien het minder bijwerkingen veroorzaakt, een betere tolerantie heeft en minder dosisaanpassingen behoeft. (Dit proefschrift)

4. Onderhoudsbehandeling met ritodrine vertraagde afgifte capsules, na aanvankelijke succes­ volle tocolyse met intraveneus toegediende ritodrine, verlaagt de kans op recidief van uterus contracties die een nieuwe intraveneuze behandeling noodzakelijk maakt of tot vroegge- boorte aanleiding geeft. (Dit proefschrift)

5. Weeënremming als behandeling van dreigende vroeggeboorte dient gecombineerd te worden met toediening van corticosteroiden ter verbetering van de foetale longrijpheid, ook in geval van gebroken vliezen.

6. Het door de overheid gehanteerde kwaliteitscriterium voor IVF - meer dan 10% doorgaande zwangerschappen per behandelingscyclus - is verwerpelijk indien daaraan niet wordt toege­ voegd een maximum voor het aantal veroorzaakte meerlingen.

7. Jongens worden vaker te vroeg geboren dan meisjes. (Cooperstock, Obstet. Gynecol. 1996:88; 189.)

8. Het aantal aanvragen voor euthanasie is omgekeerd evenredig met de geleverde zorg.

9. IVF is een heel normale behandeling. (D.Braat, Volbkrant 20-06-1996)

10. If your job is something you love, you'll never work a day in your life. (Winston Churchill)

11. Een verstandige meid krijgt haar kind op tijd!

12. Beurzen zijn er voor promovendi, niet voor hoogleraren. (Prof. dr. R. van der Ploeg, Voltekrant 15-01-1996) 13. Een premature bevalling bestaat niet; wel een prematuur kind en een preiaterme partus.

14. Indien de begroting van de medisch specialistische zorg wordt gedekt volgens de werkwijze van het huidige kabinet stijgt de prijs van de benzine.