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MISOPROSTOL
FOR THE
INDUCTION OF LABOUR AT TERM
Jodie Michele Dodd
M.B.B.S., F.R.A.N.Z.C.O.G., C.M.F.M.
Thesis submitted in fulfilment of the requirements for the degree of
Doctor of Philosophy, March 2005
Department of Obstetrics & Gynaecology
Faculty of Health Sciences
The University of Adelaide
TABLE OF CONTENTS TABLE OF CONTENTS ............................................................................................... 2 LIST OF TABLES.......................................................................................................... 6 LIST OF FIGURES........................................................................................................ 8 GLOSSARY OF TERMS............................................................................................... 9 ABSTRACT................................................................................................................... 10 DECLARATION .......................................................................................................... 12 ACKNOWLEDGEMENTS ......................................................................................... 13 AUTHOR’S CONTRIBUTION................................................................................... 15 1. LITERATURE REVIEW ........................................................................................ 16 1.1 INDUCTION OF LABOUR – AN OVERVIEW ................................................. 16
1.1(1) Introduction ...................................................................................................... 16 1.1(2) Historical Perspective....................................................................................... 16 1.1(3) Prostaglandins .................................................................................................. 17 1.1(4) Role of Prostaglandins in the Initiation of Labour........................................... 18 1.1(5) The Role of Prostaglandins in Cervical Ripening............................................ 21 1.1(6) Therapeutic use of Prostaglandins to Induce Labour ....................................... 22 1.1(7) The Cochrane Systematic Reviews of Induction of Labour ............................ 23
1.2 MISOPROSTOL..................................................................................................... 25 1.2(1) Chemistry and Development............................................................................ 25 1.2(2) Stability ............................................................................................................ 26 1.2(3) Metabolism and Pharmacokinetics .................................................................. 26 1.2(4) Toxicity and Teratogenicity ............................................................................. 27
1.3 MISOPROSTOL FOR THE INDUCTION OF LABOUR................................. 28 1.3(1) Introduction ...................................................................................................... 28 1.3(2) Research Methodology..................................................................................... 32 1.3(3) Misoprostol for Induction of Labour – Results from the current Cochrane Systematic Reviews .................................................................................................... 33 1.3(4) Uterine Hyperstimulation................................................................................. 36 1.3(5) Limitations of the Current Clinical Trials of Misoprostol ............................... 39 1.3(6) Essential Features of Future Misoprostol Clinical Trials................................. 42
2. ORAL MISOPROSTOL VERSUS VAGINAL PROSTAGLANDIN E2 FOR THE INDUCTION OF LABOUR AT TERM – A SYSTEMATIC REVIEW AND META-ANALYSIS....................................................................................................... 44 2.1 INTRODUCTION .................................................................................................. 44 2.2 METHODS.............................................................................................................. 44
2.2(1) Types of studies................................................................................................ 44 2.2(2) Types of participants ........................................................................................ 44 2.2(3) Types of interventions...................................................................................... 45 2.2(4) Types of outcome measures ............................................................................. 45 2.2(5) Search strategies for identification of studies .................................................. 46 2.2(6) Methods of the review...................................................................................... 46
2.3 RESULTS ................................................................................................................ 47 2.3(1) Description of Studies ...................................................................................... 47
2.3(2) Meta-analysis ................................................................................................... 50 2.4 DISCUSSION.......................................................................................................... 53
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2.5 CONCLUSIONS ..................................................................................................... 55 3. MISOPROSTOL FOR CERVICAL RIPENING AND INDUCTION OF LABOUR IN WOMEN WITH INTACT MEMBRANES AT TERM: A RANDOMISED CONTROLLED TRIAL.................................................................. 56 3.1 INTRODUCTION .................................................................................................. 56 3.2 STUDY AIMS & HYPOTHESES......................................................................... 57 3.3 METHODS.............................................................................................................. 57
3.3(1) Trial Design...................................................................................................... 57 3.3(2) Inclusion Criteria.............................................................................................. 58 3.3(3) Exclusion Criteria............................................................................................. 58 3.3(4) Randomisation Schedule.................................................................................. 58 3.3(5) Blinding............................................................................................................ 59 3.3(6) Treatment Allocation ....................................................................................... 59 3.3(7) Treatment Schedules ........................................................................................ 59 3.3(8) Study Outcome Measures ................................................................................ 61 3.3(9) Data Collection................................................................................................. 63 3.3(10) Statistical Analysis ......................................................................................... 63 3.3(11) Sample Size.................................................................................................... 63
3.4 RESULTS ................................................................................................................ 64 3.4(1) Baseline Characteristics ................................................................................... 64 3.4(2) Primary Outcomes............................................................................................ 66 3.4(3) Secondary Outcomes – Evidence of Effect...................................................... 67
3.4(4) Secondary Outcomes – Labour and Birth Complications................................ 68 3.4(5) Secondary Outcomes - Neonatal Complications.............................................. 69 3.4(6) Secondary Outcomes - Maternal Complications.............................................. 70 3.4(7) Pre-specified Secondary Analyses – Effect of Maternal Parity and Bishop’s Score at Trial Entry..................................................................................................... 71
3.5 DISCUSSION.......................................................................................................... 79 3.6 CONCLUSION ....................................................................................................... 83 4. WOMEN’S PREFERENCES FOR CARE ............................................................ 85 4.1 INTRODUCTION .................................................................................................. 85 4.2 STUDY AIMS AND HYPOTHESES.................................................................... 85 4.3 METHODS.............................................................................................................. 85 4.4 RESULTS ................................................................................................................ 87
4.4(1) Baseline characteristics .................................................................................... 87 4.4(2) Women’s Satisfaction and Preferences for Care at Discharge......................... 87 4.4(3) Women’s Likes and Dislikes During Induction of Labour at Discharge......... 88 4.4(4) Midwives' Satisfaction and Preferences for Care............................................. 90 4.4(5) Women’s Satisfaction and Preferences for Care at 6 weeks Postpartum......... 90 4.4(6) Women’s Likes and Dislikes During Induction of Labour at 6 weeks Postpartum .................................................................................................................. 92
4.5 DISCUSSION.......................................................................................................... 93 4.6 CONCLUSION ....................................................................................................... 95 5. TIME OF COMMENCING INDUCTION OF LABOUR – A NESTED RANDOMISED CONTROLLED TRIAL.................................................................. 96 5.1 INTRODUCTION .................................................................................................. 96 5.2 STUDY AIMS AND HYPOTHESES.................................................................... 97
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5.3 METHODS.............................................................................................................. 97 5.3(1) Trial Design...................................................................................................... 97 5.3(2) Inclusion and Exclusion Criteria ...................................................................... 98 5.3(3) Randomisation Schedule.................................................................................. 98 5.3(4) Blinding............................................................................................................ 98 5.3(5) Treatment Allocation ....................................................................................... 99 5.3(6) Treatment Schedules ........................................................................................ 99 5.3(7) Study Outcome Measures .............................................................................. 100 5.3(8) Data Collection............................................................................................... 100 5.3(9) Statistical Analysis ......................................................................................... 100 5.3(10) Sample Size.................................................................................................. 101
5.4 RESULTS .............................................................................................................. 101 5.4(1) Baseline Characteristics ................................................................................. 101 5.4(2) Time of Commencing Induction and Primary Outcomes .............................. 103 5.4(3) Time of Commencing Induction - Secondary Outcomes: Evidence of Effect.................................................................................................................................. 105 5.4(4) Time of Commencing Induction – Secondary Outcomes: Labour and Birth Complications ........................................................................................................... 107 5.4(5) Time of Commencing Induction – Secondary Outcomes: Neonatal Complications ........................................................................................................... 111 5.4(6) Time of Commencing Induction – Secondary Outcomes: Maternal Complications ........................................................................................................... 112 5.4(7) Time of Commencing Induction – Women’s Satisfaction and Preferences for Care at Discharge...................................................................................................... 113 5.4(8) Time of Commencing Induction - Women’s Likes and Dislikes at Discharge.................................................................................................................................. 114 5.4(9) Time of Commencing Induction – Women’s Satisfaction and Preferences for Care at 6 weeks Postpartum...................................................................................... 116 5.4(10) Time of Commencing Induction - Women’s Likes and Dislikes at 6 weeks Postpartum ................................................................................................................ 117
5.5 DISCUSSION........................................................................................................ 118 5.6 CONCLUSION ..................................................................................................... 120 6. COST COMPARISON........................................................................................... 122 6.1 INTRODUCTION ................................................................................................ 122 6.2 STUDY HYPOTHESES....................................................................................... 122 6.3 METHODS............................................................................................................ 123 6.4 RESULTS .............................................................................................................. 124 6.5 DISCUSSION........................................................................................................ 131 6.6 CONCLUSION ..................................................................................................... 132 7. MISOPROSTOL FOR INDUCTION OF LABOUR AT TERM – AN UPDATED META-ANALYSIS................................................................................. 133 7.1 INTRODUCTION ................................................................................................ 133 7.2 STUDY AIMS AND HYPOTHESES.................................................................. 133 7.3 METHODS............................................................................................................ 133 7.4 RESULTS .............................................................................................................. 134
7.4(1) Description of Studies .................................................................................... 134 7.4(2) Meta-analysis ................................................................................................. 134
7.5 DISCUSSION........................................................................................................ 139
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7.6 CONCLUSION ..................................................................................................... 140 8. OVERALL CONCLUSIONS ................................................................................ 141 8.1 ORAL MISOPROSTOL VERSUS VAGINAL PROSTAGLANDIN E2 GEL FOR INDUCTION OF LABOUR............................................................................. 141 8.2 WOMEN’S PREFERENCES FOR CARE ........................................................ 142 8.3 TIME OF ADMISSION FOR INDUCTION OF LABOUR............................. 142 8.4 COSTS ASSOCIATED WITH INDUCTION OF LABOUR........................... 143 8.5 IMPLICATIONS FOR CLINICAL PRACTICE.............................................. 144 8.6 IMPLICATIONS FOR RESEARCH.................................................................. 146 REFERENCES............................................................................................................ 148
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LIST OF TABLES
Table 2.3(1)Description of Included Studies.................................................................. 48 Table 2.3(2)(i) Meta-analysis of primary outcomes ....................................................... 51 Table 2.3(2)(ii) Meta-analysis of secondary outcomes – evidence of effect.................. 51 Table 2.3(2)(iii) Meta-analysis of secondary outcomes – maternal complications........ 52 Table 2.3(2)iv Meta-analysis of secondary clinical outcomes – neonatal complications .........................................................................................................................................52 Table 3.3(8)(ii) Secondary outcomes.............................................................................. 62 Table 3.4(1) Comparison of baseline variables at trial entry.......................................... 65 Table 3.4(2) Primary Outcomes...................................................................................... 66 Table 3.4(3) Secondary Outcomes – Evidence of Effect................................................ 67 Table 3.4(4) Secondary Outcomes – Labour & Birth Complications ............................ 69 Table 3.4(5) Secondary Outcomes - Neonatal Complications ....................................... 70 Table 3.4(6) Secondary Outcomes - Maternal Complications ....................................... 71 Table 3.4(7)(i) Distribution of maternal parity and initial Bishop’s score ..................... 72 Table 3.4(7)(ii) Secondary Analysis – Primary Outcomes............................................. 73 Table 3.4(7)(iii) Secondary Analysis – Evidence of Effect............................................ 75 Table 3.4(7)(iv) Secondary Analysis – Labour & Birth Complications......................... 76 Table 3.4(7)(vi) Secondary Analysis – Maternal Complications ................................... 79 Table 4.4(2) Women’s Satisfaction and Preferences for Care at Discharge .................. 88 Table 4.4(3) Women’s Likes and Dislikes During Induction of Labour at Discharge... 89 Table 4.4(4) Midwives’ Satisfaction and Preferences for Care...................................... 90 Table 4.4(5) Women’s Satisfaction and Preferences for Care at 6 weeks Postpartum .. 91 Table 4.4(6) Women’s Likes and Dislikes During Induction of Labour at 6 weeks Postpartum ...................................................................................................................... 93 Table 5.4(1) Distribution of Time of Commencing Induction ..................................... 103 Table 5.4(2) Time of Commencing Induction - Primary Outcomes............................. 104 Table 5.4(3) Time of Commencing Induction - Secondary Outcomes: Evidence of Effect............................................................................................................................. 106 Table 5.4(4) Time of Commencing Induction – Secondary Outcomes: Labour and Birth Complications ............................................................................................................... 108 Table 5.4(5) Time of Commencing Induction – Secondary Outcomes: Neonatal Complications ............................................................................................................... 111 Table 5.4(6) Time of Commencing Induction – Secondary Outcomes: Maternal Complications ............................................................................................................... 113 Table 5.4(7) Time of Commencing Induction of Labour – Women’s Satisfaction and Preferences for Care at Discharge ................................................................................ 114 Table 5.4(8) Time of Commencing Induction - Women’s Likes and Dislikes at Discharge ...................................................................................................................... 115 Table 5.4(9) Time of Commencing Induction – Women’s Satisfaction and Preferences for Care at 6 weeks Postpartum .................................................................................... 116 Table 5.4(10) Time of Commencing Induction - Women’s Likes and Dislikes at 6 weeks Postpartum ......................................................................................................... 118
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Table 6.3(1) Costs to the Women’s and Children’s Hospital for Induction of Labour 124 Table 6.4(1) Costs for all women ................................................................................. 125 Table 6.4(2) Costs nulliparous women with Bishop’s score 0-3.................................. 126 Table 6.4(3) Costs for nulliparous women with Bishop’s score 4-6 ............................ 127 Table 6.4(4) Costs for multiparous women with Bishop’s score 0-3 ........................... 128 Table 6.4(5) Costs for multiparous women with Bishop’s score 4-6 ........................... 129 Table 7.4(1) Summary characteristics of the current randomised trial......................... 134 Table 7.4(2)(i) Meta-analysis of Primary Outcomes .................................................... 135 Table 7.4(2)(ii) Meta-analysis of Secondary Outcomes – Evidence of Effect ............. 137 Table 7.4(2)(iii) Meta-analysis of Secondary Outcomes - Maternal Complications.... 138 Table 7.4(2)(iv) Meta-analysis of Secondary Outcomes – Neonatal Complications ... 138
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LIST OF FIGURES Figure 1.1(3) Prostaglandin structure and nomenclature................................................ 18 Figure 1.2(1)(i) Structure of misoprostol and prostaglandin E1 ..................................... 25 Figure 1.2(1)(ii) Development of misoprostol................................................................ 26 Figure 1.3(5)(i) Absorption profile of oral misoprostol tablets and misoprostol solution........................................................................................................................................ 41 Figure 3.4(1) Trial Flow Chart ....................................................................................... 64 Figure 5.4(1) Trial Flow Chart ..................................................................................... 102 Figure 6.4(1) Drug Costs per Woman Induced............................................................. 130 Figure 7.4(2)(i) Vaginal birth not achieved in 24 hours ............................................... 136 Figure 7.4(2)(ii) Uterine hyperstimulation with associated fetal heart rate changes.... 136 Figure 7.4(2)(iii) Caesarean section.............................................................................. 136 Figure 7.4(2)(iv) Cervix unchanged after 12/24 hours ................................................. 137 Figure 7.4(2)(v) Need for oxytocin infusion ................................................................ 137
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GLOSSARY OF TERMS
PG prostaglandin
HPMC hydroxy propyl methyl cellulose
HPLC high pressure liquid chromatography
RIA radio immune assay
mg milligrams
mcg micrograms
mL millilitres
RCT randomised controlled trial
RR relative risk
OR odds ratio
NNTH number needed to treat to harm
95% CI 95% confidence intervals
IOL induction of labour
GA gestational age
ARM artificial rupture of membranes
SROM spontaneous rupture of membranes
PROM premature rupture of membranes
PE pre-eclampsia
HT hypertension
IUGR intra-uterine growth restriction
APH antepartum haemorrhage
CTG cardiotocograph
MSL meconium stained liquor
EDB epidural block
NVD normal vaginal delivery
CS caesarean section
PPH postpartum haemorrhage
NICU neonatal intensive care unit
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ABSTRACT
Background:
The aims of this randomised, double blind, placebo controlled trial were to compare
vaginal PGE2 gel with oral misoprostol in the induction of labour at term.
Methods:
Women randomised to the oral misoprostol group received 20mcg oral misoprostol
solution at two hourly intervals and placebo vaginal gel, and those in the vaginal
prostaglandin group received vaginal PGE2 gel at six hourly intervals and oral placebo
solution.
The primary outcome measures were vaginal birth not achieved in 24 hours, uterine
hyperstimulation with associated fetal heart rate changes, and caesarean section.
Women were asked about their preferences for care, and a cost comparison was
performed for the two methods of induction of labour. A nested randomised trial
compared health outcomes for the woman and her infant related to morning or evening
admission for commencing induction of labour.
Results:
A total of 741 women were randomised, 365 to the misoprostol group and 376 to the
vaginal PGE2 group.
There were no differences between women in the oral misoprostol group and women in
the vaginal PGE2 group, for the outcomes vaginal birth not achieved in 24 hours
(Misoprostol 168/365 (46.0%) versus PGE2 155/376 (41.2%); RR 1.12 95% CI 0.95-
1.32; p=0.134), caesarean section (Misoprostol 83/365 (22.7%) versus PGE2 100/376
(26.6%); RR 0.82 95% CI 0.64-1.06; p=0.127), or uterine hyperstimulation with fetal
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heart rate changes (Misoprostol 3/365 (0.8%) versus PGE2 6/376 1.6%); RR 0.55 95%
CI 0.14-2.21; p=0.401).
Women in the misoprostol group were more likely to indicate that they “liked
everything” associated with their labour and birth experience compared with women in
the vaginal PGE2 group (Misoprostol 126/362 (34.8%) versus PGE2 103/373 (27.6%);
RR 1.26; 95% CI 1.02-1.57; p=0.036).
There were no differences in the primary outcomes when considering morning or
evening admission to commence induction.
The use of misoprostol was associated with a saving of $110.83 per woman induced.
Conclusions:
The use of oral misoprostol in induction of labour does not lead to poorer health
outcomes for women or their infants, women express greater satisfaction with their
labour and birth experience, and with misoprostol induction there is a cost saving to the
institution.
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DECLARATION
This work contains no material which has been accepted for the award of any other
degree or diploma in any other university or tertiary institution, and, to the best of my
knowledge and belief, contains no material previously published or written by another
person, except where due reference has been made in the text.
I give consent to a copy of my thesis, when deposited in the University Library, being
available for loan and photocopy.
Jodie Dodd
March 2005
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ACKNOWLEDGEMENTS I must begin by thanking the 741 women who have selflessly participated in this clinical
research project, in the hope of improving health care for women and their infants.
I first encountered my supervisors Professors Jeffrey Robinson and Caroline Crowther,
as a 4th year medical student. Their enthusiasm for research and clinical obstetrics
inspired me then, and more recently have shaped my career path. I am extremely
grateful for the opportunity to have them both as mentors and colleagues, and hope that
in the future I might emulate the high standards they set as clinicians, researchers, and
teachers.
A project like this doesn’t happen without the assistance and support of many, and I
would like to say an enormous thank you to the following people.
• Sheree Agett (research midwife) – for her fantastic efforts with recruitment, data
collection, follow-up of postnatal questionnaires, and the preparation of
treatment packs.
• Judy Coffey and the midwifery team on delivery suite – for their incredible
support, without which this trial would not have been possible.
• The midwives in antenatal clinic, and the obstetric medical staff – for promoting
the trial in a positive way to eligible women.
• Professor Gus Dekker and the staff at the Lyell McEwin Health Service, and Dr
Dirk Ludwig and the staff of the Hervey Bay Hospital, for their support and
involvement in the trial.
• Kristyn Willson – for her statistical assistance, advice, and patience in dealing
with a novice in the realms of statistical programming.
• Staff in the Maternal & Perinatal Clinical Trials Unit – for their support and
willingness to share the highs and lows that life has to offer.
• The Department of Obstetrics & Gynaecology, The University of Adelaide –for
the opportunity to study in such a great department (and for the desk with the
wonderful view across the park).
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Any research project requires funding and I would like to thank the following
institutions for their financial assistance.
• The Department of Obstetrics and Gynaecology, The University of Adelaide for
financial assistance and provision of support services.
• The Women’s and Babies Division of the Women’s and Children’s Hospital, for
meeting the cost of drugs.
• The South Australian & Northern Territory branch of the Royal Australian and
New Zealand College of Obstetricians and Gynaecologists for their generous
donation of $2,500 for consumable items.
• Mayne Health for the provision of the Mayne Women’s Health Fellowship,
through the Research Foundation of the Royal Australian and New Zealand
College of Obstetricians and Gynaecologists.
• The Women’s and Children’s Hospital Research Foundation for the provision of
a Postgraduate Medical Scholarship, and Project Grant to facilitate research into
women’s and infant’s health.
There are a few more people who have been instrumental in shaping the person I am,
and whose love and support is immeasurable.
• Thank you to my family and friends – your support means everything.
• Thank you to Mum, Dad and Nana – you have always supported me in
everything I have done and for this I am so grateful. I hope that you are proud of
my achievements, and of the person you have helped me to become.
• Thank you to Greg – you are my best friend, my lover and my soul mate. I thank
you for your unending belief in me and in my ability, for your constant support
and encouragement, and for being the person who makes life so worthwhile.
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AUTHOR’S CONTRIBUTION I have been responsible for the development of the original protocols, submission of
these protocols to Research and Ethics Committees, and obtaining funding for the
project. I have devised the information sheets and data sheets, and have coordinated in-
service education sessions for midwifery and medical staff. I have been involved in the
preparation of treatment packs, recruitment at the Women’s and Children’s Hospital,
data collection at that site, checking of all data forms and data entry. I have received
statistical advice and software programme assistance from Kristyn Willson, but the
interpretation and any errors therein are my responsibility.
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1. LITERATURE REVIEW
1.1 INDUCTION OF LABOUR – AN OVERVIEW
1.1(1) Introduction
Induction of labour is a common obstetric intervention, performed when the perceived
risks to the mother or fetus associated with continuation of the pregnancy are greater
than those associated with birth (Riskin-Mashiah 1999). Labour may be induced for
medical or obstetric indications (such as hypertensive conditions, impaired glucose
tolerance, prolonged pregnancy, intrauterine growth restriction), or for the convenience
of mother or obstetrician (so called “social” indications).
In Australia, 26.6% of pregnant women had their labour induced in 2002 (Laws 2004).
In South Australia 29.3% of pregnancies were induced for the same year (Laws 2004),
with the rate of induction remaining relatively stable over the past 10 years (Chan
1999). It is estimated that prostaglandins are used in approximately 22.5% of all
confinements to induce labour (Nassar 2000).
1.1(2) Historical Perspective
An early literature record of induction of labour dates to the 1500’s, with a mixture of
juniper berries, cinnamon, and castor oil recommended to expedite birth (Calder 1997).
During the 18th century, the concept of induction of labour was to effect early birth for
women with a contracted pelvis (O'Dowd 1994), with midwives aware of the use of
ergot as an induction agent (Davis 1935). Ergot is a fungal agent that principally attacks
rye and other grains, but when eaten prompted gastrointestinal disturbances (Davis
1935). John Stearns reported the use of ergot in the medical literature in 1808, where a
preparation was mixed with boiling water and administered to labouring women,
thereby hastening the onset of contractions (Stearns 1808). Its use was often associated
with marked gastrointestinal symptoms (Stearns 1808), and an increase in the
occurrence of stillbirth caused its use to fall into disrepute (O'Dowd 1994). Almost a
century later, Henry Dale noted that a preparation from ox pituitary tissue initiated
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uterine contractions in a pregnant cat (Dale 1906), with Blair Bell subsequently
describing the clinical use of pituitary extract in pregnant women for the management
of “normal labour”, and uterine atony post-partum (Bell 1909). Davis and colleagues
went on to extract the active component from ergot alkaloids, further demonstrating the
compound’s uterotonic effects (Davis 1935), with du Vigneaud later identifying both
oxytocin and vasopressin in pituitary extracts, allowing purification and the synthetic
preparation of Syntocinon in 1953 (du Vigneaud 1953). While initial oxytocin
preparations were crude and unreliable in effect, the development of Syntocinon
allowed intravenous titration to produce a more predictable and effective method of
induction of labour.
The state of the cervix relates directly to the duration of pregnancy, as described by
Bishop, who published a quantitative pelvic scoring system based on 500 consecutive
vaginal examinations performed on multiparous women who entered labour
spontaneously after 36 weeks gestation (Bishop 1964). Subsequent clinical studies have
shown correlation between outcome of induction of labour and cervical score, with the
use of amniotomy and oxytocin infusion in the presence of an “unfavourable” cervix (as
indicated by a low Bishop score), being associated with a longer interval to delivery and
a high incidence of caesarean section (Calder 1974; Calder 1975; MacKenzie 1978).
This has resulted in the search for more effective agents in the induction of labour
designed to ‘ripen’ the cervix, and reduce the risk of caesarean section due to a “failed”
induction of labour.
1.1(3) Prostaglandins
The existence of prostaglandins was established through the observations of Kurzrok
and Lieb in 1930, who noted the ability of human semen to initiate uterine contractions
(Kurzrok 1930). After isolating substances from the male prostate gland shown to
initiate contractions of uterine tissue, von Euler named the compounds
“prostaglandins”, believing them to be a unique secretion from that gland (von Euler
1936). It was not until later that prostaglandins were recognised as a large family of
substances ubiquitous in mammalian biology (Collins 1990; Calder 1997).
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Prostaglandins consist of 20-carbon fatty acid molecules derived from dietary fatty
acids, and consisting of a pentane ring with a fatty acid moiety attached at two adjacent
carbons (Elattar 1978; Embrey 1981; Garris 1989; O'Brien 1995) (Figure 1.1(3)).
Prostaglandins are classified into six groups (A to F), according to the structure or
substitution of the pentane ring. The numbering sequence begins at the carboxylic end
and proceeds around the ring to the terminal carbon (Elattar 1978; Garris 1989). The
subscript numeral (1,2,3) indicates the number of double bonds in the fatty acid
backbone (Elattar 1978; Garris 1989; O'Brien 1995). For example, prostaglandins of the
E series consist of a ketone group at the C9 position, and a hydroxyl group at the C11
position (Elattar 1978; Garris 1989). Prostaglandin E1 has a trans double bond between
C13 and C14, while prostaglandin E2 has an additional cis double bond at the C5-C6
position (Elattar 1978; Collins 1985).
Figure 1.1(3): Prostaglandin structure and nomenclature (Collins 1985)
1.1(4) Role of Prostaglandins in the Initiation of Labour
The initiation of labour in sheep has been well studied, with a role for the fetal pituitary-
adrenal system established (Liggins 1967; Liggins 1968; Liggins 1973). These findings
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have not been replicated in women, with a local membrane mechanism controlling the
production of prostaglandins being favoured (Liggins 1977).
The presence of prostaglandins E and F has been demonstrated in amniotic fluid
samples obtained from women at term with spontaneous rupture of the membranes and
shown to cause muscle obtained from the pregnant uterus to contract (Karim 1966),
while amniotic fluid obtained in early pregnancy induces a relaxant effect (Karim
1967). Prostaglandin F2α and its metabolite can be detected in blood prior to the onset of
uterine contractions (Karim 1969), and exert a stimulatory effect on myometrial
contractility in vivo following intravenous infusion to women in both early and late
pregnancy (Embrey 1969).
The concentrations of prostaglandins in amniotic fluid increase with the onset of labour
(Keirse 1973; Hibbard 1974; Hillier 1974; Keirse 1974; Dray 1976; Keirse 1977;
itchell 1977; Mitchell 1978; Whalen 1978), with increasing cervical dilatation (Keirse
ue, and amnion and chorion, with a greater
oncentration of PGE2 compared with PGF2α in all tissues studied (Willman 1976b). At
M
1973; Keirse 1974; Keirse 1977), and have been shown to be lower following induction
of labour when compared with spontaneous onset of labour (Hillier 1974; Keirse 1974;
Willman 1976a; Husslein 1981). Levels are also lower where there is poor progression
of cervical dilatation (Keirse 1977; Reddi 1987). Accurate estimates of prostaglandin
concentrations in amniotic fluid samples following artificial rupture of the membranes
is difficult, as the procedure itself has been documented to generate an increase in
prostaglandin production (Mitchell 1976; Keirse 1977; Mitchell 1977). The increasing
PGF concentrations seen from 36 weeks gestation in amniotic fluid obtained following
ARM, were not demonstrated when samples at similar gestation were obtained from
amniocentesis, suggesting a role for the local control of production of these compounds
in the pregnant uterus (Mitchell 1976).
Prostaglandin concentrations have been measured in samples of umbilical cord,
placental, decidual and myometrial tiss
c
term, the concentration of PGE2 increased most in decidual tissue with the onset of
labour, being greater again when labour occurred spontaneously (Willman 1976a). The
distribution and concentration of enzymes regulating prostaglandin degradation within
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the pregnant uterus reflect this, being highest in the fetal membranes and placenta,
followed by the myometrium and decidua, with the lowest levels being found in the
mbilical cord (Keirse 1975). No significant prostaglandin metabolism has been
s obtained from caesarean sections performed between 38
nd 40 weeks gestation show the greatest concentration of EP and FP receptors at the
lower doses in a dose response fashion, while the effect at higher doses is
hibitory (Senior 1993).
u
demonstrated in the amniotic fluid (Keirse 1975). An increase in prostaglandin
production in the decidua and amnion has been documented following treatment with
oxytocin (Fuchs 1981), as has oxytocin induced release of arachidonic acid (the
precursor required for prostaglandin synthesis) from decidual cells obtained from
women in labour at term (Wilson 1988).
For prostaglandins to exert a biological effect, there must be interaction with receptors
specific to the type of prostaglandin, as determined by the structure of the pentane ring.
However, there is no differentiation between molecules that differ in their fatty acid
backbone, and both prostaglandin E1 and E2 will interact with the same PGE receptor
(O'Brien 1995).
The receptor site specific for prostaglandins of the E series have been designated EP
receptors, and those interacting with prostaglandins of the F series, FP receptors (Senior
1993). The EP receptor has been further subdivided into subclasses EP1 to EP3 (Senior
1993). Myometrial sample
a
uterine fundus, with a decrease in receptor concentration towards the cervix,
corresponding with a decrease in the content and distribution of uterine smooth muscle
(Senior 1993). Stimulation of the FP receptor by PGF2α has been shown to initiate a
purely contractile response of the myometrium, while stimulation of the EP receptor by
PGE2 is stimulatory at low doses and inhibitory at higher doses (Senior 1993).
Stimulation of EP2 receptors produces a relaxant effect on the myometrium when
stimulated by high concentrations of PGE2, while the EP3 receptor initiates a contractile
response when stimulated by low doses of PGE2 (Senior 1993). Misoprostol an EP1 and
EP3 receptor agonist, initiates a qualitative response similar to PGE2 in that contractions
are initiated at
in
20
Prostaglandin receptors are present in significant numbers in both the pregnant and non-
pregnant uterus, rendering it sensitive to prostaglandin stimulation throughout
pregnancy (O'Brien 1995). In contrast, oxytocin receptor concentration in the
myometrium increases between 100 and 200 fold as gestation advances (Fuchs 1984;
O'Brien 1995), reaching a maximum during early labour (Fuchs 1984). This increase in
receptor concentration is paralleled by an increase in uterine sensitivity to oxytocin
during the second half of gestation (Fuchs 1984). Oxytocin may play a dual role in
parturition, activating myometrial receptors resulting in uterine contraction, and also
stimulating prostaglandin production in decidual tissue expressing oxytocin receptors
(Fuchs 1984).
1.1(5) The Role of Prostaglandins in Cervical Ripening
The historical view of the cervix as a muscular structure with sphincteric properties was
challenged by Danforth, whose study of pregnant and non-pregnant surgical specimens
indicated the cervix to be composed of fibrous connective tissue, interspersed with
small amounts of smooth muscle (Danforth 1947). Cervical specimens obtained from
non-pregnant women demonstrate a primarily collagenous connective tissue
component, the bundles woven tightly together and held with a “cementing substance”,
while those obtained from women in late pregnancy revealed increased tissue oedema,
with spaces between the individual collagen fibres, and increased diameter of individual
pared with the non-pregnant cervix, the postpartum
cervix has an increased water, glycosaminoglycan, and hyaluronic acid content
dermatan and
cess, in which infiltrating macrophages and
neutrophils release proteolytic enzymes including collagenase (Liggins 1981; Kelly
ocess may involve initiation of a vascular
fibres (Danforth 1960). When com
(Danforth 1974), in addition to a reduction in the concentration of
chondroitan sulfate, and fewer bridges between collagen fibrils, resulting overall in a
loose and disorganised network of fibres (Uldberg 1983). An increase in the local
production of prostaglandins from cervical tissue obtained during late pregnancy
suggests a role for the cervical softening and dilatation observed during late pregnancy
and labour (Ellwood 1980). Changes to the structure of the cervix may be further
mediated by an inflammatory pro
1994). The role of prostaglandins in this pr
response and the infiltration of leukocytes.
21
1.1(6) Therapeutic use of Prostaglandins to Induce Labour
Natural prostaglandins are unsuitable for therapeutic use, by virtue of their rapid
metabolism (as indicated by a short duration of action when given parenterally and a
lack of activity when given orally); numerous side effects (including facial flushing,
headaches, hyperthermia, hypotension, shivering, and the more commonly observed
gastrointestinal symptoms of nausea, vomiting, and diarrhoea); and chemical instability
at room temperature (Collins 1990).
Prostaglandins were first used clinically to induce labour in the late 1960’s (Karim
1968), with subsequent administration of both E and F series prostaglandins to induce
labour via intravenous infusion at or near term (Bygdeman 1968; Karin 1968; Karim
brey 1970; Karim 1970a), or to induce first trimester abortion (Embrey 1970;
Karim 1970b; Wiqvist 1970). While oral prostaglandins have been administered to
of intravaginal PGE2 gel or pessaries (MacKenzie 1977;
acKenzie 1978; Gordon-Wright 1979; Shepherd 1979; MacKenzie 1981; Shepherd
1981).
1969; Em
induce labour, their use was limited by the frequent occurrence of side effects reflecting
the high doses required to produce clinical effect (Karim 1971; Craft 1972; Gordon-
Wright 1979). In an attempt to reduce side effects, local vaginal application of
prostaglandins became the route of administration of choice, initially involving extra-
amniotic placement (Calder 1974; Shepherd 1976; Calder 1977), although similar
results (in terms of effective induction of labour) were achieved with the less
cumbersome approach
M
Regardless of the route of administration of prostaglandins, be it oral, intravenous, or
intravaginal, the effect in terms of cervical ripening is similar (O'Brien 1995). Local
vaginal administration of PGE2 results in systemic absorption, with maximal uterine
activity correlating with the peak circulatory level of the compound (O'Brien 1986;
O'Brien 1995). In this regard then, the appropriate route of prostaglandin administration
should be determined by both cost and ease of administration, in addition to preferences
expressed by women.
22
1.1(7) The Cochrane Systematic Reviews of Induction of Labour
A standardised protocol has been developed by the Cochrane Pregnancy and Childbirth
Collaborative Review Group to facilitate review of the randomised controlled trial
literature concerning methods of induction of labour (Hofmeyr 2005a). The protocol
includes the use of standard primary outcome measures, including vaginal birth not
chieved within 24 hours (including women who birth vaginally beyond 24 hours and
f clinical effect includes the cervix remaining unchanged or unfavourable
fter 12 to 24 hours and need for oxytocin administration. Complications relate to both
f scarred and unscarred uteri, while asymptomatic
dehiscence of the uterine scar identified incidentally at the time of surgery was
a
by caesarean section); caesarean section; uterine hyperstimulation with fetal heart rate
changes; neonatal morbidity and mortality; and maternal morbidity and mortality.
Uterine hyperstimulation has been defined as either uterine tachysystole (the presence
of five or more contractions in a ten minute period for more than two consecutive ten
minute periods) or uterine hypertonus (the presence of a uterine contraction lasting for
more than two minutes) (Curtis 1987). The fetal heart rate changes considered as
abnormal include fetal tachycardia (fetal heart rate of greater than 160 beats per
minute); fetal bradycardia (fetal heart rate of less than 110 beats per minute); reduced
variability of the fetal heart rate (less than five beats per minute); and persistent
decelerations of the fetal heart rate (RANZCOG 2001; RCOG 2001).
Secondary outcome measures have also been reported in the protocol in a standardised
fashion. These include evidence of clinical effect, complications, and satisfaction.
Evidence o
a
mother and infant, including uterine hyperstimulation without fetal heart rate changes;
uterine rupture; use of epidural analgesia; instrumental vaginal birth; meconium stained
liquor; Apgar score of less than seven at five minutes; admission to the neonatal
intensive care unit; neonatal encephalopathy; perinatal death; childhood disability;
maternal side effects (including nausea, vomiting, and diarrhoea); postpartum
haemorrhage; serious maternal complications and maternal death. Measures of
satisfaction relate to both woman and caregiver. Uterine rupture was defined as all
clinically significant ruptures o
excluded.
23
Intravenous prostaglandin for the induction of labour is associated with an increase in
uterine hyperstimulation, both with (5 trials; 390 participants; RR 6.76; 95% CI 1.23-
37.11) and without (5 trials; 318 participants; RR 4.25; 95% CI 1.48-12.24) fetal heart
rate changes (Luckas 2005). As intravenous prostaglandins are no more efficient than
oxytocin in effecting vaginal birth within 24 hours (9 trials; 990 participants; RR 0.85;
95% CI 0.61-1.18), but have both increased maternal side effects (8 trials; 940
articipants; RR 3.75; 95% CI 2.46-5.70) and cost, its use in the induction of labour has
been abandoned (Luckas 2005).
Vaginal prostaglandins are effective in the induction of labour, increasing the likelihood
of vaginal birth within 24 hours of the induction process commencing (2 trials; 384
participants; RR 0.19; 95% CI 0.14-0.25), and reducing the need for oxytocin
augmentation (11 trials; 1265 participants; RR 0.80; 95% CI 0.69-0.91), without
increasing the rate of caesarean section (32 trials; 6243 participants; RR 0.79; 95% CI
0.79-1.00) when compared with placebo (Kelly 2005). Vehicle delivery of the
preparation indicates that PGE2 gel is as efficacious as PGE2 vaginal tablets, but
relatively more expensive. Vaginal prostaglandin E2 is currently the standard
prostaglandin agent in most obstetric hospitals within Australia for cervical ripening
and induction of labour.
p
Oral PGE2 has been shown to be no more clinically effective than intravenous oxytocin
in achieving vaginal birth within 24 hours (1 trial; 201 women; RR 3.09; 95% CI 0.13-
74.96), but more frequently associated with gastrointestinal side effects of vomiting (3
trials; 305 participants; RR 5.56; 95% CI 2.15-14.38) and diarrhoea (2 trials; 236
participants; RR 8.13; 95% CI 1.03-63.94) (French 2005). The use of oral PGE2 in the
induction of labour has been replaced with vaginal prostaglandin preparations, although
the availability of misoprostol has regenerated interest in an oral route of
administration.
24
1.2 MISOPROSTOL
1.2(1) Chemistry and Development
Misoprostol is a synthetic prostaglandin structurally related to prostaglandin E1 (PGE1),
and is the generic name for (+/-) methyl, 11α, 16-dihydroxy-16-methyl-oxoprost-13E-
en-1-oate, a water insoluble, oily, viscous substance (Garris 1989) (Figure 1.2(1)(i)).
Figure 1.2(1)(i): Structure of Misoprostol and Prostaglandin E1 (Collins 1990)
While natural PGE1 is an effective inhibitor of gastric acid secretion when administered
intravenously, there are a number of disadvantages to its use in the therapeutic treatment
of peptic ulcer disease, including a lack of oral activity, short duration of action, and
side effects including rhinorrhoea, trembling, nausea, vomiting, and diarrhoea (Collins
1985). Misoprostol was developed from attempts to manipulate PGE1 to produce an
orally active compound while minimising side effects.
The proposed lack of oral activity of PGE1 is thought to relate to the rapid metabolic
oxidation of the C15 hydroxyl group (Collins 1985). The placement of a methyl group at
the C15 position blocks this oxidative process, the resulting compound having long
acting inhibition of gastric acid secretion, as well as potency when administered orally
(Collins 1985). A reduction in side effects typical of prostaglandins while maintaining
the antisecretory potency of PGE1 was achieved by repositioning the beta side chain
from the C15 to C16 position. However, this compound was only weakly active after oral
administration, and had a short duration of action. The addition of a methyl group to the
C16 position gave misoprostol, a compound with increased oral potency and duration of
action (Figure 1.2(1)(ii)).
25
Figure 1.2(1)(ii): Development of misoprostol (Collins 1990)
1.2(2) Stability
Like all prostaglandins of the E series, misoprostol is chemically unstable at room
mperature (Collins 1985; Karim 1987; Collins 1990; Kararli 1991). Under alkaline or
acidic conditions in the presence of a small amount of water, a dehydration process
to produce an A-type prostaglandin
cokinetics
te
occurs, with elimination of the 11-hydroxyl groups
(PGA) (Collins 1990; Chen 2000). Under similar conditions, PGA can further isomerise
to a prostaglandin-B form (Collins 1990; Chen 2000). The stability of misoprostol is
significantly improved by its dispersion (1:100) in hydroxy propyl methyl-cellulose
(HPMC) (Kararli 1991). The presence of the HPMC matrix separates the misoprostol
molecules, reducing the mobility of both misoprostol and water. Additionally, any water
present preferentially interacts with the hydroxyl groups in the HPMC, sparing
interaction with, and resulting in minimal degradation of misoprostol (Kararli 1991).
1.2(3) Metabolism and Pharma
After oral administration, misoprostol is rapidly de-esterified to misoprostol acid, which
is the major active metabolite in plasma (Garris 1989). This rapid conversion occurs
before or during absorption, and as a result, the plasma concentration of misoprostol is
virtually undetectable, even shortly after administration (Garris 1989). Misoprostol acid
26
is in turn metabolised via β and σ oxidation to inactive dinor and tetranor metabolites
that are excreted renally, with the total urinary excretion of unchanged misoprostol
being less than 1% of the orally administered dose (Garris 1989). The dinor metabolite
has only weak antisecretory activity, while the tetranor metabolite has no substantial
antisecretory activity (Garris 1989).
isoprostol incubated in human plasma
absorption of total radioactivity occurring
genicity
The in vitro half-life for the de-esterification of m
at 37 degrees Celsius is 6.4 minutes, with
within 1.5 hours, and a mean elimination half-life for total plasma radioactivity of 1.7
hours (+/- 0.06) (Schoenhard 1985). In vivo, the mean peak plasma concentration of
misoprostol acid is achieved within 12 minutes with an elimination half-life of 20
minutes, and on the basis of radioactive excretion in both urine and faeces, it has been
estimated that an average of 88% of the oral dose of misoprostol is absorbed (Karim
1987). Misoprostol acid is 81-89% protein bound, primarily by serum albumin
(Nicholson 1990; Foote 1995).
1.2(4) Toxicity and Terato
ical trials assessing acute toxicity of misoprostol were performed in rats,
ice and dogs, with the most common clinical signs observed being diarrhoea, emesis,
tremor, and reduced motor activity (Kotsonis 1985). Most of the deaths occurred within
24 hours, while those animals surviving regained “normal” behaviour and appearance
within 3 to 4 days. These studies indicated a safety margin of 500 to 1000 fold between
the lethal doses observed in animals, and the therapeutic doses administered to humans.
Carcinogenic and fertility properties were studied in rats, mice and rabbits, without
demonstration of any effects attributable to misoprostol (Kotsonis 1985), the conclusion
being that misoprostol showed no evidence of embryotoxicity, fetotoxicity, or
teratogenicity (Kotsonis 1985).
The preclin
m
27
1.3 MISOPROSTOL FOR THE INDUCTION OF LABOUR
1.3(1) Introduction
Misoprostol is licensed for use in the treatment of gastric ulcer disease, and does not
have a product license for use in pregnancy in Australia, or any other country
worldwide. Despite this, its use in obstetric and gynaecological practice has increased,
being used widely in the management of first and second trimester abortion (Dickinson
1999), and in the third trimester of pregnancy following intrauterine fetal death
(Mariani-Neto 1987). While misoprostol is used commonly in this setting, comparison
of clinical outcomes with other methods of induction of labour to terminate pregnancy,
the optimal route of administration, and the optimal dosing regimen have not been
assessed systematically. More recently, misoprostol has been used in the induction of
labour at term in the presence of a viable fetus, with both vaginal (Hofmeyr 2005b) and
oral (Alfirevic 2005) routes of administration being used. There have also been trials of
misoprostol as an oxytocic agent in the management of the third stage of labour
(Gulmezoglu 2005).
1.3(1)(i) Safety of Misoprostol
1.3(1)(i)(a) Misoprostol and Uterine Rupture Concern has been raised regarding the
use of misoprostol as an induction agent, with several case reports of uterine rupture
and its consequences (including maternal or fetal death) appearing in the literature
(Phillips 1996; Bennett 1997; Cunha 1999; Plaut 1999; Daisley 2000; Gherman 2000;
Akhan 2001; Al-Hussaini 2001; Berghahn 2001; Khabbaz 2001). These reports have
involved women with scarred and unscarred uteri, following oral and vaginal
administration of misoprostol, and where the induction was performed in the presence
of a live fetus and following intrauterine demise. Doses of the drug have varied from
those generally considered to be low (25mcg) (Bennett 1997; Plaut 1999; Gherman
2000), up to 600mcg being used in cases of fetal demise (Phillips 1996).
Attempts have been made to address the issue of the safety of misoprostol in the
presence of a uterine scar, with both Sciscione (1998) and Wing (1998) commencing
randomised controlled trials. Sciscione (1998) compared 50mcg intravaginal
28
misoprostol at four hourly intervals with an intracervical Foley catheter, in which
women with a prior caesarean birth were not excluded. While one woman with a
scarred uterus suffered uterine rupture following misoprostol, it is not clear from the
report the total number of women randomised, the number of women with a scarred
uterus who were involved, or the number of women allocated to each treatment arm.
Wing and colleagues specifically recruited women with a prior caesarean birth to a
randomised controlled trial comparing 25mcg vaginal misoprostol at six hourly
intervals with intravenous oxytocin for induction of labour (Wing 1998). Both
symptomatic scar rupture and asymptomatic scar dehiscence were combined as a single
outcome measure. Seventeen women were allocated to the misoprostol group, and 21
women to the oxytocin group. Two women in the misoprostol group were identified
with scar disruption (11.8%), and due to concerns regarding the safety of misoprostol in
this clinical setting, the trial was terminated prematurely.
The safety of misoprostol for the induction of labour in women with a previous
caesarean birth is unlikely to be addressed in the short term, with only two of the trials
(Chuck 1995; Webb 1997) included in the systematic reviews of vaginal misoprostol
(Hofmeyr 2005b) and oral misoprostol (Alfirevic 2005) in the induction of labour
involving women with a previous caesarean section.
1.3(1)(i)(b) Misoprostol and gastrointestinal stimulation Concern has been raised
related to the use of misoprostol and the occurrence of meconium stained amniotic fluid
during labour induction (Hofmeyr 2003). There is evidence from in vitro animal studies
to indicate the stimulation of ileal smooth muscle by both dinoprostone and misoprostol
(Matonhodze 2002), postulated to result in the fetal passage of meconium. However, the
systematic reviews of both vaginal (Hofmeyr 2005b) and oral (Alfirevic 2005)
misoprostol in the induction of labour provide some reassurance about the safety of
misoprostol, particularly in relation to the presence of meconium stained liquor.
1.3(1)(ii) Clinical Toxicity of Misoprostol
There have been two reported cases in the literature of overdose with misoprostol in
pregnancy (Bond 1994; Austin 1997).
29
Bond and Van Zee (1994) report a case of a woman at 31 weeks gestation who
presented having taken 6000mcg misoprostol in combination with trifluoperazine in a
suicide attempt. Two hours after ingestion, she complained of shortness of breath and
chills, and was noted to be febrile with a tetanic uterus. Initial laboratory investigations
were consistent with a metabolic acidosis and hypoxaemia. An obstetric ultrasound
performed one hour after initial presentation confirmed fetal death, and the woman gave
birth to an appropriately grown stillborn infant four hours after ingestion. Nine hours
after ingestion the woman’s temperature returned to normal limits, and she remained
asymptomatic prior to discharge three days after presentation.
Austin and colleagues (1997) report the case of a woman at 36 weeks gestation who
self-administered 6000mcg of misoprostol intravaginally and 600mcg orally to induce
labour. Three hours after ingestion at the time of presentation, she complained of chills,
cramping pain, nausea and vomiting. Examination confirmed an elevated temperature, a
firm uterus suggestive of tonic uterine activity, and fetal demise. Initial laboratory
investigations revealed a picture of metabolic acidosis and hypoxaemia, which
progressed to a disseminated intravascular coagulopathy (DIC), with evidence of
placental abruption at birth. Over the course of admission, her symptoms resolved and
she was discharged several days after presentation.
Similar symptoms have been reported in an elderly woman who consumed 3000mcg of
misoprostol orally (Graber 1991).
1.3(1)(iii) Cost of Misoprostol
Despite these safety concerns, the use of misoprostol as an induction agent has
increased rapidly, related in part to its low cost when compared with other prostaglandin
preparations commonly employed in obstetric practice. The current cost to the
Women’s and Children’s Hospital for a 1mg dose of prostaglandin E2 gel is
(Aus)$40.17, with the cost of a 2mg dose increasing to (Aus)$51.64. The total cost to
the hospital for the 1998/1999 financial year for prostaglandin gel alone was
(Aus)$48,307, and for the 1999/2000 financial year (Aus)$38,508. In contrast a single
200mcg misoprostol tablet costs 35 cents.
In addition to the obvious cost differential between misoprostol and prostaglandin E2
gel, there are other costs associated with induction of labour. Several authors have
30
attempted to elucidate these differences further (Sanchez-Ramos 1993; Wing 1995a;
Sanchez-Ramos 1997). In comparing vaginal misoprostol with intracervical
prostaglandin E2 gel, Wing estimated misoprostol induction of labour to be associated
with a saving of (US)$163 per woman induced in drug costs (Wing 1995a). Sanchez-
Ramos compared the average induction costs of vaginal misoprostol with intravenous
oxytocin alone, and with PGE2 gel followed by oxytocin infusion (Sanchez-Ramos
1993). The average induction costs for drugs alone was (US)$49 per woman given
misoprostol, increasing to (US)$205 for those women receiving oxytocin alone, and
(US)$315 for those women administered PGE2 gel followed by oxytocin infusion. In a
subsequent report, the authors compared misoprostol with dinoprostone inserts, with the
average induction costs increasing to (US)$606 per woman with the use of dinoprostone
inserts (Sanchez-Ramos 1997). Kramer compared intravenous oxytocin with vaginal
misoprostol in a more detailed analysis that considered costs of intrapartum care for
both vaginal and caesarean birth, epidural analgesia, post-partum care, and newborn
nursery costs (Kramer 1997). The mean hospital charge per woman administered
misoprostol was significantly less than for women induced with oxytocin infusion
(US$2081 +/- $984 (misoprostol) versus US$2616 +/- $1035 (oxytocin); p<0.005).
The use of misoprostol as an induction agent has significant potential for reduction in
both drug and hospital care costs for developed nations, in addition to providing an
economical method of induction of labour in under resourced countries. A further
advantage in this setting relates to its chemical stability at room temperature, obviating
the need for refrigerated storage as is required with other obstetric prostaglandin
compounds, in settings where this may be unavailable or unreliable.
While hospital administrators and health economists could make an impressive
argument supporting the use of misoprostol as an induction agent, it is unlikely that this
will propel manufacturers towards seeking appropriate product licensing for the use of
misoprostol in pregnancy. There is considerable economic advantage to health service
providers in the use of misoprostol for induction of labour, although its low production
cost does not translate into financial incentives for the manufacturers.
31
1.3(2) Research Methodology
The randomised controlled trial (RCT) is accepted widely as the ‘gold standard’ in
clinical research methodology, allowing comparison between alternate interventions or
forms of care (Chalmers 1989; Greenhalgh 1997c). Any differences observed between
alternate forms of care may be due to true differences in the care received, or
differences in the pre-treatment characteristics of the individuals involved in the trial
(Chalmers 1989). The ability to attribute differences in observed outcome to the actual
form of treatment given relies on the extent to which trial participants are comparable in
every respect, with the exception of the treatment received (Chalmers 1989). The RCT
theoretically reduces systematic bias through the selection of a sample of participants
from a particular population and then randomly allocating them to different
interventions (Greenhalgh 1997a; Greenhalgh 1997c).
The relationship between randomisation and the estimate of treatment effect has been
assessed, with non-randomised clinical trials distorting apparent effects of care in both
directions, ranging from an underestimation of effect of 75% to an overestimation of
160% (Kunz 1998). The effect of a randomised control group with historical controls
has also been investigated, the use of historical controls being more likely to be
associated with significant differences between the study groups in favour of the
treatment group, and generally having poorer outcome measures than randomised
controls (Sacks 1982). Thus it is not surprising that the use of historical control groups
is more likely to yield statistically significant differences between treatments than those
trials using randomised controls (Chalmers 1983).
Another source of bias in clinical trials is the effect of knowledge of the treatment
allocation by participants, caregivers and those assessing outcome. This form of bias
can be reduced by blinding all involved to the treatment allocated (Chalmers 1989).
Inadequate allocation concealment has been shown to be associated with a 40% increase
in the estimate of treatment effect (Kunz 1998), with a similar exaggeration of effect
present in trials where there was inadequate allocation concealment or where there was
no formal attempt of blinding (Schulz 1995).
32
1.3(3) Misoprostol for Induction of Labour – Results from the current
Cochrane Systematic Reviews
1.3(3)(i) Vaginal Misoprostol for Induction of Labour The Cochrane Systematic Review assessing vaginal misoprostol for cervical ripening
and induction of labour at term included 70 randomised controlled trials in which
misoprostol was compared with placebo, intravenous oxytocin, vaginal prostaglandin
E2, and intracervical prostaglandins (Hofmeyr 2005b). Of these 70 trials, only 13 were
double blind and placebo controlled (Fletcher 1993; El-Azeem 1997; Farah 1997;
Surbek 1997; Gottschall 1998; Ramsey 1998; Srisomboon 1998; Diro 1999;
Montealegre 1999; Stitely 2000; Khoury 2001; Ferguson 2002; Meydanli 2003).
Overall, women who were administered misoprostol were less likely not to achieve
vaginal birth within 24 hours (7 trials; 1580 participants; RR 0.76; 95% CI 0.68-0.85),
but at the expense of increased uterine hyperstimulation with fetal heart rate changes
(11 trials; 1607 participants; RR 2.28; 95% CI 1.33-3.93), when compared with vaginal
prostaglandins (Hofmeyr 2005b). While doses of more than 25 micrograms at four
hourly intervals were “more effective” than conventional methods of induction of
labour, it was at the expense of greater occurrence of uterine hyperstimulation. In
contrast, lower doses of misoprostol were considered “as effective” as standard
prostaglandin preparations, but without an increase in uterine contractile disorders. The
authors indicate a need for further trials with appropriate blinding, further assessment of
low doses of misoprostol, and of sufficient size to be able to detect differences in rare
but clinically important complications (Hofmeyr 2005b).
1.3(3)(ii) Oral Misoprostol for Induction of Labour
The current Cochrane Systematic Review of oral misoprostol in the induction of labour
included 13 randomised controlled trials (Alfirevic 2005), in which oral misoprostol
was compared with placebo, intravenous oxytocin, vaginal prostaglandin E2,
intracervical prostaglandin E2, and vaginal misoprostol. Of these 13 trials, only four
were double blind and placebo controlled, one comparing oral misoprostol with placebo
(Ngai 1996); one comparing oral misoprostol with vaginal prostaglandin E2 (Tessier
1997); and two comparing oral with vaginal misoprostol (Adair 1998; Bennett 1998).
33
1.3(3)(ii)(a) Oral Misoprostol versus Placebo A single randomised placebo controlled
trial was identified, in which a single 200mcg oral dose of misoprostol was compared
with placebo in women with pre-labour ruptured membranes at term (Ngai 1996).
Women allocated to the misoprostol group were less likely to require oxytocin
augmentation (1 trial; 80 participants; RR 0.25, 95% CI 0.10-0.60), had the
randomisation to delivery interval reduced by 8.7 hours (1 trial; 80 participants; WMD
–522.00 minutes; 95% CI –683.72 to –360.28) when compared with placebo. There was
no difference observed in caesarean births (1 trial; 80 participants; RR 1.05, 95% CI
0.23-4.90), or uterine hyperstimulation with associated fetal heart rate changes (1 trial;
80 participants; RR 3.15; 95% CI 0.13-75.09). However, the trial had a small sample
size and the confidence intervals around the treatment effect are wide.
1.3(3)(ii)(b) Oral Misoprostol versus Intravenous Oxytocin Two trials have compared
oral misoprostol with intravenous oxytocin infusion (Butt 1999; Ngai 2000). Women
allocated to the misoprostol groups were administered 50mcg at four hourly intervals
(Butt et al. 1999), and 100mcg at four hourly intervals (Ngai 2000).
The meta-analysis of these two trials indicated no differences between the interventions
with regards to caesarean birth (2 trials; 188 participants; RR 0.97, 95% CI 0.43-2.22)
or uterine hyperstimulation with associated fetal heart rate changes (2 trials; 188
participants; RR 0.96, 95% CI 0.25-3.66).
1.3(3)(ii)(c) Oral Misoprostol versus Vaginal Prostaglandin E2 Two trials have
compared oral misoprostol with vaginal prostaglandin E2 involving a total of 962
women. In one study, women were allocated to either the standard vaginal
prostaglandin regimen or to 50mcg oral misoprostol, both administered at six hourly
intervals, to a maximum of four doses (200mcg misoprostol) in a 24-hour period
(Tessier 1997). In the other, women were randomly allocated to either vaginal
dinoprostone gel, or to a titrated oral misoprostol solution, with the initial dose being
20mcg, and increased to 40mcg if no clinical effect was observed after two or three
doses (Hofmeyr 2001).
The meta-analysis of these two trials indicates no differences between the interventions
regarding vaginal birth not achieved in 24 hours (1 trial; 691 participants; RR 1.19; 95%
34
CI 0.94-1.51), caesarean birth (2 trials; 959 participants; RR 0.90; 95% CI 0.70-1.17),
or uterine hyperstimulation with associated fetal heart rate changes (2 trials; 929
participants; RR 0.87, 95% CI 0.49-1.56).
1.3(3)(ii)(d) Oral Misoprostol versus Vaginal Misoprostol Seven trials have compared
oral misoprostol with vaginal misoprostol, involving differing dosing intervals and
regimens (Alfirevic 2005). The dose of oral misoprostol ranged from 50mcg at four
hourly intervals (Bennett 1998; Wing 1999b; Dyar 2000; Shetty 2001), up to 100mcg at
three hourly intervals (Toppozada 1997) and 200mcg at six hourly intervals (Adair
1998).
The meta-analysis performed (Alfirevic 2005) indicated women receiving oral
misoprostol were more likely to remain undelivered vaginally after 24 hours (4 trials;
877 participants; RR 1.27, 95% CI 1.09-1.47). However, oral administration of
misoprostol was associated with fewer caesarean births (7 trials; 1276 participants; RR
0.77, 95% CI 0.61-0.97), while there were no differences observed in uterine
hyperstimulation and route of administration (6 trials; 1236 participants; RR 1.1, 95%
CI 0.78-1.47).
1.3(3)(iii) Implications
While both of these reviews have included a total of 83 trials, only 17 of the trials have
been appropriately blinded and placebo controlled. In particular, only four of the trials
involving an assessment of oral misoprostol have involved appropriate blinding of
participants, caregivers and outcome assessors. With women and their caregivers aware
of the allocated treatment in 80% of the trials conducted to date, there is potential for
the introduction of bias in these results. To improve the quality of evidence available,
and the certainty with which differences between treatment groups can be attributed to
medication differences, further randomised controlled trials are required, but with the
essential inclusion of an appropriate placebo control in order to maintain blinding.
1.3(4) Uterine Hyperstimulation
Uterine hyperstimulation is recognised as a potential complication following
prostaglandin induction of labour, with concern that frequent uterine contractions may
35
impair utero-placental perfusion, manifesting as abnormalities of the fetal heart rate.
The terminology surrounding uterine hyperstimulation has been one of confusion,
including both uterine tachysystole and uterine hypertonus (Curtis 1987). Additionally,
uterine hyperstimulation may be associated with fetal heart rate changes, or may occur
in isolation. Management of uterine hyperstimulation has involved the use of
intravenous or subcutaneous beta-mimetic therapy (Egarter 1990). However,
management practices are inconsistent, with some practitioners treating
hyperstimulation in the absence of fetal heart rate changes, while others reserve therapy
for cases complicated by fetal heart rate abnormalities.
The occurrence of uterine hyperstimulation is well described following misoprostol
induction of labour (Hofmeyr 1998; Hofmeyr 2005b). This is particularly the case
following vaginal administration of misoprostol, with uterine hyperstimulation (both
with and without fetal heart rate changes) occurring more frequently when compared
with oxytocin and vaginal prostaglandin E2 (Hofmeyr 2005b). In an attempt to
determine any effect of dose on the occurrence of hyperstimulation, lower dosing
regimens (defined as 25mcg or less at four hourly or less intervals) have been compared
with higher dosing regimens (Hofmeyr 2005b). The use of lower doses of misoprostol
was not associated with an increase in the number of women who did not achieve
vaginal birth within 24 hours (RR 1.04, 95% CI 0.92-1.18), although more women
required oxytocin augmentation (RR 1.23, 95% CI 1.08-1.40). There were no
differences observed between the regimens with regards to caesarean birth (RR 1.00,
95% CI 0.79-1.26), meconium stained liquor (RR 0.89, 95% CI 0.66-1.22), or maternal
side effects (RR 0.71, 95% CI 0.46-1.11). Women administered lower doses of
misoprostol were less likely to experience uterine hyperstimulation, both with (RR 0.50,
95% CI 0.36-0.71) and without (RR 0.61, 95% CI 0.49-0.76) fetal heart rate changes,
with trends towards fewer infants with Apgar scores of less than seven at five minutes
(RR 0.76, 95% CI 0.40-1.45), and fewer neonatal intensive care unit admissions (RR
0.82, 95% CI 0.64-1.05).
Wing has suggested that there may be a cumulative effect of misoprostol contributing to
the occurrence of uterine hyperstimulation (Wing 1995a). A dose of 50mcg vaginal
misoprostol administered at 3 hourly intervals resulted in 21 of 25 women experiencing
uterine tachysystole (Wing 1995a). In subsequent trials, the dose of misoprostol was
36
reduced (Wing 1995b), and the dosing interval increased to four (Wing 1996) and six
hours (Wing 1997). When 25mcg of misoprostol was administered, nine women
developed tachysystole after the first dose, with the average interval to onset being 303
minutes (Wing 1995b). An additional 11 women developed tachysystole after the
second dose of misoprostol, with the interval to onset reduced to 169 minutes.
Increasing the dosing interval from three to six hours (Wing 1996) revealed a
statistically non-significant decrease in the occurrence of tachysystole from 14.6%
(three hourly intervals) to 11.2% (six hourly intervals). There was no difference in the
interval from last dose to onset of tachysystole with either regimen.
These observed effects are in keeping with information obtained from pharmacokinetic
studies performed in early pregnancy termination, where misoprostol was administered
both orally and vaginally (Zieman 1997; Danielsson 1999). In a study comparing oral
and vaginal absorption of misoprostol, two cohorts, each of 10 women were recruited,
in which five were pregnant and five not (Zieman 1997). One cohort was administered
400mcg of misoprostol orally, while the other received 400mcg of misoprostol
vaginally. Following oral administration, the plasma concentration of misoprostol acid
rose quickly, peaking between 12.5 and 60 minutes (34 +/- 17 minutes) after
administration, and falling steeply by 120 minutes. In contrast, the plasma concentration
of misoprostol acid after vaginal administration rose gradually to reach a maximum
level between 60 and 120 minutes (80 +/- 27 minutes), thereafter declining slowly to an
average of 61% of the peak level, 240 minutes after administration. The incidence of
side effects with misoprostol was similar between the two routes of administration,
although numbers were too small for statistical comparison. The bioavailability of
vaginal misoprostol was three times greater than that achieved with oral administration,
as determined by the area under the concentration curve. Peak plasma levels were
slightly lower, obtained more gradually, and persisted for longer duration when
misoprostol was administered vaginally rather than orally.
Absorption of 200 and 400mcg doses of misoprostol has been compared following oral
and vaginal routes of administration, and correlated with effects on uterine contractility
(Danielsson 1999). Thirty women presenting for first trimester termination of
pregnancy were recruited between 8 and 11 weeks gestation and received either 200mcg
(5 women received oral administration and 6 women received vaginal administration),
37
or 400mcg (10 women with oral administration and 9 women with vaginal
administration) of misoprostol. Intrauterine pressure was measured via a Grass
polygraph connected to a pressure transducer. At the end of the monitoring period,
pregnancy was terminated by suction curettage. Misoprostol was absorbed more quickly
after oral administration, with plasma levels peaking after 30 minutes. In contrast,
plasma levels after vaginal administration rose more gradually, reaching a peak 1-2
hours after administration, and remained detectable for a longer period. Independent of
the route of administration, misoprostol treatment was associated with an increase in
uterine tonus. This effect was more rapid following oral administration (mean onset of
effect 7.8 minutes +/- 3 minutes), with maximal effect being seen after a mean of 25.5
minutes (+/- 5.0 minutes). In contrast, the onset of uterine contractility following
vaginal administration was seen after 20.9 minutes (+/- 5.3 minutes), with maximal
effect after 46.3 minutes (+/- 20.7 minutes). Uterine activity was more pronounced 2
hours after vaginal administration when compared with oral administration, the effect
being even greater 4 hours after administration. This study reported no difference in
effect (in terms of strength of uterine activity) between the two doses of misoprostol
when administered via the same route.
The bioavailability of misoprostol administered vaginally is greater than when
administered orally (Zieman 1997; Danielsson 1999). However, vaginal absorption of
misoprostol is influenced by pH, an effect studied using litmus paper at sterile speculum
examination prior to induction of labour (Gunalp 2000). Women with vaginal pH of less
than 5 were found to have a shorter induction to birth interval and required fewer doses
of misoprostol, when compared with women whose vaginal pH was greater than 5. This
difference in birth interval was thought to reflect the improved liquefaction of
misoprostol in an acidic medium (Singh 1999). The usual pH of the vagina during
pregnancy is less than 4.5, due to the production of lactic acid by normal vaginal
bacterial commensals (Gravett 1994). However, the vaginal environment can be
changed, particularly in association with vaginal infection and following membrane
rupture, resulting in alterations in pH (Gravett 1994).
The studies described above (Zieman 1997; Danielsson 1999) have involved women in
early pregnancy following oral doses of misoprostol varying from 200 to 400 mcg.
There have been no studies to date assessing the absorption kinetics of smaller doses of
38
oral misoprostol, which would be more relevant to its potential use as an agent to induce
labour at term, where doses of 50mcg or less may be more appropriate.
Based on this information, an oral route of administration may be preferable to vaginal
administration in the induction of labour. Vaginal administration has been complicated
by high rates of uterine tachysystole, with evidence of a cumulative effect over time, as
indicated by the shorter interval to onset of hyperstimulation following second and
subsequent doses. This is in keeping with the pharmacokinetic profile of vaginally
administered misoprostol, with levels 60% of the peak value obtained 240 minutes after
vaginal administration. The potential advantage of an oral route of administration,
despite reduced bioavailability when compared with vaginal administration, is the rapid
peak in plasma levels, with the maximal peak in increased uterine tonus occurring at
this point (Danielsson 1999). Additionally, the concentrations of the drug in plasma
decreases quickly by 120 minutes after administration, reducing adverse effects
secondary to drug accumulation. An oral dosing interval of two hours should allow for
maximal plasma concentrations to be achieved (and therefore maximal increase in
uterine tonus), reduced drug accumulation (and therefore reduced adverse effects such
as uterine hyperstimulation), and allow the lowest possible dose to be administered to
each woman while maintaining clinical effect.
1.3(5) Limitations of the Current Clinical Trials of Misoprostol
1.3(5)(i) Dose Administered
The majority of clinical trials to date involving misoprostol for induction of labour at
term have used doses between 50 and 200mcg. Low doses of misoprostol (less than
25mcg) have specifically been compared with higher doses (greater than 25mcg) in a
sub-group analysis (Hofmeyr 2005b). The use of lower doses of misoprostol was not
associated with a reduction in clinical efficacy (that is achieving vaginal birth within 24
hours of the induction commencing), indicating that further attention be directed to
assessment of both clinical effect and side effects of even lower doses of misoprostol, in
an attempt to determine the lowest clinically effective dose.
The investigation of low doses of misoprostol has been hampered to a large extent by
the currently available commercial preparation of misoprostol, which is manufactured
39
as 100 and 200mcg scored tablets. Several studies have used 25mcg of misoprostol,
obtained by manual quartering of a 100mcg tablet (Varaklis 1995; Wing 1996; Wing
1997; Clark 1998; Wing 1998; Wing 1999a). Dosage variation in attempting to use
25mcg misoprostol has been assessed in which one hundred microgram tablets were
scored to produce a 50mcg half tablet that was further halved to yield a 25mcg
fragment, and compared using both freehand razor blade and pill cutter techniques
(Williams 2001; Williams 2002). These tablet fragments were then assessed for
usability, including weight and assay for misoprostol content using liquid
chromatography. While the mean fragment weights were not different between the two
methods of cutting, there was greater variance among those pills cut with pill cutter
(SD+/-5.8) when compared with those cut using the razor blade (SD+/-2.6) (Williams
2002). The cumulative weight recovery of tablet fragments was higher for tablets
divided with the razor blade, with 99% of the original tablet recovered compared with
96.6% when using the pill cutter (Williams 2002). Misoprostol content as determined
by liquid chromatography indicated that 62% of assayed tablet fragments were within
10% of the expected 25mcg dose, 25% varied between 10 and 20%, and 12% were
more than 20% of the expected dose (Williams 2002). While the authors concluded that
manual quartering of a standard 100mcg misoprostol tablet produced an accurate low-
dose form of misoprostol (Williams 2002), it necessitates weighing of each individual
tablet fragment prior to administration.
In an attempt to overcome this difficulty and still administer a low dose (20mcg),
misoprostol has been administered as a solution (Hofmeyr 2001). A 200mcg
commercially available tablet was dispersed in 200mL water, producing a solution with
misoprostol concentration 1mcg/mL. Women were then administered 20mL of solution
orally. The bioavailability of oral misoprostol tablets relative to an oral solution has
been investigated, where subjects were administered a 400mcg commercial tablet
orally, as well as 400mcg of misoprostol / HPMC dispersion in solution (Karim 1987).
The absorption profile of the two preparations was indistinguishable (Karim 1987)
(Figure 1.3(5)(i)).
40
Figure 1.3(5)(i): Absorption profile of oral misoprostol tablets and misoprostol
solution (Karim 1987)
Legend: Circles = administration of two 200mcg misoprostol tablets; squares = administration 400mcg
misoprostol in solution.
There is currently no pharmacokinetic data available detailing the long-term stability of
misoprostol in solution. Misoprostol solution has been made up immediately prior to
administration, and also administered as a 20mL aliquot of the same solution used for a
maximum of 12 hours (Hofmeyr 2001). In this trial, measured outcomes were similar
across sites, indicating indirectly that misoprostol was not significantly degraded
chemically in solution for a period of at least 12 hours. Making a fresh solution prior to
each administration is a time consuming process, and additionally discards 80mcg of
misoprostol in the remaining solution, which may have economic implications
particularly in under-resourced countries.
1.3(5)(ii) Oral Route of Administration
The use of oral misoprostol in the induction of labour has been under-investigated to
date, with the majority of randomised controlled trials assessing vaginal misoprostol.
This is in part due to the increased bioavailability of misoprostol when administered
vaginally, and the subsequent likelihood of achieving vaginal birth within 24 hours of
the induction process commencing, when compared with oral administration (RR 1.27,
95% CI 1.09-1.47) (Alfirevic 2005). The increased ‘speed’ of the labour and birth
process has to be balanced against the reduction in caesarean birth (RR 0.77, 95% CI
0.61-0.97) observed following oral administration (Alfirevic 2005). An oral route of
administration has advantages of ease and convenience for both woman and caregiver,
41
with the potential to administer small frequent doses in a controlled fashion to attain
clinical effect, while minimising unwanted side effects.
1.3(5)(iii) Comparison of Misoprostol with the Current Standard Preparation
Oral misoprostol has been compared with placebo (Ngai 1996), intravenous oxytocin
(Butt 1999; Ngai 2000), vaginal prostaglandin E2 (Tessier 1997; Hofmeyr 2001),
intracervical prostaglandin E2 (Bartha et al. 2000), and vaginal misoprostol (Toppozada
1997; Adair 1998; Bennett 1998; Wing 1999a; Dyar 2000; Shetty 2001). Neither oral
nor vaginal misoprostol are the current standard methods of cervical ripening and
induction of labour in most obstetric units. Misoprostol should therefore be compared
with the current standard – vaginal prostaglandin E2 gel for women with intact
membranes, and intravenous oxytocin for women with pre-labour ruptured membranes.
1.3(6) Essential Features of Future Misoprostol Clinical Trials
1.3(6)(i) Randomised Trials with Placebo Control
As indicated previously, the randomised controlled trial is the “gold standard” in
clinical research methodology. While there have been randomised trials assessing
misoprostol, the majority of these trials have not included a placebo control.
The commercial preparation of misoprostol limits the suitability of other similar
appearing tablets that can safely be administered during pregnancy for use as a placebo.
If misoprostol is crushed to a powder for administration as a dispersed solution, it is
possible (although time consuming) to develop a similar appearing placebo solution.
Similarly, the appearance of the dinoprostone applicator requires transfer of
dinoprostone under sterile conditions into a syringe that can be used for the placebo gel
also. While both of these procedures are cumbersome, it is possible to develop an
appropriate oral and vaginal placebo.
1.3(6)(ii) Investigation of the Lowest Effective Clinical Dose
The majority of trials of misoprostol have utilised doses between 50 and 200mcg, due to
its commercial preparation as 100 and 200mcg scored tablets. The use of misoprostol
dispersed in solution makes it possible to administer low doses in a convenient manner
for women and their caregivers.
42
1.3(6)(iii) Broad Inclusion Criteria
In order to apply the results of any trial to the wider population concerned, the inclusion
criteria must closely reflect the wider population. Induction of labour is performed for
indications where there is compromise of either maternal or fetal condition. Trial
inclusion criteria should therefore aim to include these women, as it is important to have
information regarding the use of misoprostol in these clinical settings prior to its
widespread introduction into clinical practice.
1.3(6)(iv) Increased Information Regarding Safety
While misoprostol appears to be an effective agent in the induction of labour, its
widespread clinical use cannot be recommended until further information becomes
available regarding its safety. With events such as uterine rupture, severe neonatal
acidosis, and maternal and neonatal death being rare, large numbers of women will need
to be induced with misoprostol before reliable clinical information regarding these
outcomes is available.
1.3(6)(v) Assessment of Women’s Preferences for Care
A perceived advantage of the use of oral misoprostol is its ease and convenience for the
woman and her caregivers, in particular reducing the need for repeated vaginal
examinations. The use of a vaginal placebo necessitates that all women involved require
vaginal examination, a factor that may influence their overall preferences and
perception of trial participation. However, information can still be obtained regarding
preferences for oral or vaginal administration of medication for any future pregnancy
should induction of labour be required.
With these factors as a basis, the current randomised controlled trial comparing oral
misoprostol with vaginal prostaglandin E2 was planned.
43
2. ORAL MISOPROSTOL VERSUS VAGINAL PROSTAGLANDIN E2 FOR THE INDUCTION OF LABOUR AT TERM – A SYSTEMATIC REVIEW AND META-ANALYSIS
2.1 INTRODUCTION In the current Cochrane review (Alfirevic 2005), oral misoprostol has been compared
with placebo (Ngai 1996), intravenous oxytocin (Butt 1999; Ngai 2000), vaginal
prostaglandin E2 (Tessier 1997; Hofmeyr 2001), intracervical prostaglandin E2 (Bartha
2000), and vaginal misoprostol (Toppozada 1997; Adair 1998; Bennett 1998; Wing
1999a; Dyar 2000; Shetty 2001). Neither oral nor vaginal misoprostol are the current
standard methods of cervical ripening available to clinicians at the Women’s and
Children’s Hospital for the induction of labour. Misoprostol should therefore be
compared with the current standard induction agent for women with intact membranes –
vaginal prostaglandin E2 gel.
The aim of this review was to assess the benefits and harms associated with the use of
oral misoprostol for induction of labour in women at term, compared with our current
standard method of induction of labour for women with intact membranes, being
vaginal prostaglandin E2 gel.
2.2 METHODS
2.2(1) Types of studies
Published randomised controlled trials in which oral misoprostol was compared with
intravaginal prostaglandin E2.
2.2(2) Types of participants
Women undergoing induction of labour at or near term.
44
2.2(3) Types of interventions
Oral misoprostol for the induction of labour at or near term.
2.2(4) Types of outcome measures
Outcomes include those detailed in the Cochrane Review relating to all methods of
induction of labour (Hofmeyr 2005a), and include vaginal birth not achieved within 24
hours, uterine hyperstimulation with associated fetal heart rate changes, and caesarean
section (all and those for non-reassuring fetal heart rate tracing). Uterine
hyperstimulation was defined as uterine tachysystole (with five or more contractions in
a 10 minute period for two consecutive 10 minute periods) or uterine hypertonus (a
uterine contraction lasting for more than two minutes) (Curtis 1987). The fetal heart rate
changes that were recorded as abnormal included persistent decelerations, fetal
tachycardia (fetal heart rate greater than 160 beats per minute), fetal bradycardia (fetal
heart rate less than 100 beats per minute), or reduced short term variability (less than
five beats per minute) (RANZCOG 2001; RCOG 2001). Secondary outcomes relate to
evidence of effect (cervix unfavourable or unchanged after 24 hours (as assessed by a
modified Bishop’s score before and at 24 hours if not delivered); need for oxytocin
augmentation; and the induction to birth interval); complications (including uterine
hyperstimulation without fetal heart rate changes; uterine rupture; need for epidural
analgesia; instrumental vaginal birth; presence of meconium stained amniotic fluid;
infant Apgar score of less than seven at five minutes; infant admission to the neonatal
intensive care unit (and length of stay); neonatal encephalopathy; perinatal death;
serious infant morbidity; maternal side effects (including nausea, vomiting, diarrhoea,
abdominal pain); postpartum haemorrhage (greater than 600mL and greater than
1000mL; need for blood transfusion); serious maternal complications (admission to
intensive care unit, hyperpyrexia, coma); and maternal death); and satisfaction with the
induction method (woman not satisfied; and caregiver not satisfied).
Only outcomes with available data appear in the analysis table, and any other outcomes
that were not pre-stated are labelled as such.
45
2.2(5) Search strategies for identification of studies
This review used the search strategy developed by the Cochrane Pregnancy and
Childbirth Group of the Cochrane Collaboration, and involved searching the group’s
specialised register of controlled trials (CENTRAL). In addition, a MEDLINE search
was conducted using the key words misoprostol, oral; vaginal prostaglandin E2;
pregnancy, third trimester; and induction of labo(u)r. The date of last search was
February 2005. A manual search was conducted of the reference list of all identified
papers.
2.2(6) Methods of the review
Identified trials were evaluated for appropriateness for inclusion and methodological
quality without consideration of their results, according to pre-stated eligibility criteria.
Eligible trials were assessed using the following criteria for assessment of quality:
• Generation of random allocation sequence: adequate, inadequate, unclear;
• Allocation concealment: A=adequate, B=unclear, C=inadequate;
• Blinding of participants: yes, no, inadequate, no information;
• Blinding of caregivers: yes, no, inadequate, no information;
• Blinding of outcome assessment: yes, no, inadequate, no information;
• Completeness of follow-up data (including any differential loss of participants
from each group): A=<3% of participants excluded; B=3-9.9% of participants
excluded; C=10-19.9% of participants excluded; D=20% or more excluded;
E=unclear;
• Analysis of participants in randomised groups.
Data was extracted from the original papers and data from different trials were
combined if considered to be sufficiently similar. Meta-analyses were performed using
relative risks for binary outcomes, and weighted mean differences for continuous
outcomes.
46
2.3 RESULTS
2.3(1) Description of Studies
The search strategy identified seven randomised controlled trials comparing oral
misoprostol with vaginal prostaglandin E2, of which five were included, involving a
total of 1419 women (Tessier 1997; Gherman 2001; Hofmeyr 2001; Dallenbach 2003;
Shetty 2003; Shetty 2004). The dose of misoprostol varied from 20mcg at two hourly
intervals (Hofmeyr 2001; Dallenbach 2003), to 50mcg at four hourly (Gherman 2001)
or six hourly intervals (Tessier 1997), to 100mcg at four hourly intervals (Shetty 2003;
Shetty 2004).
The trial by Matonhodze and colleagues (2003) involved a three-way comparison of
Foley catheter and titrated oral misoprostol, titrated oral misoprostol alone, and vaginal
dinoprostone. The arms comparing titrated oral misoprostol alone with vaginal
dinoprostone formed part of a larger randomised trial and have been included in that
report (Hofmeyr 2001).
The trial by Windrim and colleagues (1997) was not included as the control group
consisted of “physician chosen” methods of induction, including vaginal prostaglandins,
intracervical prostaglandins, artificial rupture of membranes and oxytocin infusion, and
it was not possible to determine the numbers of women receiving each intervention.
The characteristics of the included studies are summarised in Table 2.3(1).
47
Table 2.3(1) Description of Included Studies
Trial Identification Trial Characteristics
Tessier (Tessier 1997) Participants: women with an “indication” for induction of labour
Interventions: 50mcg oral misoprostol at 6 hourly intervals vs vaginal
PGE2 at 6 hourly intervals; maximum 4 doses in 24 hour period
Sample Size: 267 women
Outcomes: caesarean birth; uterine hyperstimulation; induction to
birth interval
Randomisation: stated to be “randomly assigned” (A)
Allocation Concealment: stated to be “double blind” (A)
Blinding: stated to be “double blind”
Gherman (Gherman 2001) Methods: Trial conducted at Naval Medical Center, Portsmouth,
Virginia between December 1998 and June 1999
Participants: women with singleton gestation in cephalic presentation
at greater than 24 weeks gestation, a medical or obstetric indication
for induction of labour and Bishop score of less than 6; exclusion
criteria included Bishop score greater than 6, prior uterine incision,
fetal malpresentation, placenta praevia or unexplained vaginal
bleeding, active herpes simplex infection, estimated fetal weight
greater than 4500g or less than 2500 g, asthma or cardiovascular
disease, hypersensitivity to prostaglandins, contraindication to
prostaglandin administration, renal or hepatic dysfunction, or non-
reassuring fetal heart rate tracing
Interventions: 50mcg oral misoprostol at 4 hourly intervals vs 4mg
vaginal PGE2 at 4 hourly intervals; max. 6 doses in 24 hour period
Sample Size: 60 women
Outcomes: failure to achieve vaginal birth within 48 hours of
induction commencing; caesarean birth; uterine hyperstimulation;
induction to birth interval; need for epidural; oxytocin use; Apgar
score less than 7 at 5 minutes; meconium stained liquor
Randomisation: computer generated random number table with
variable blocks (A)
Allocation Concealment: sequentially numbered, sealed opaque
envelopes (A)
Blinding: participants, caregivers and outcome assessors not blinded
to treatment allocation
48
Trial Identification Trial Characteristics
Hofmeyr (Hofmeyr 2001) Methods: Trial conducted Coronation & Chris Hani Baragwanath
Hospitals (South Africa), & The Liverpool Women’s Hospital (UK)
Participants: women with a singleton pregnancy in cephalic
presentation; exclusion criteria included gestational age less than 34
weeks, prior caesarean birth, uncontrolled diabetes mellitus, antepartum
haemorrhage, pre-eclampsia, eclampsia, “fetal distress”
Interventions: 20mcg oral misoprostol solution at 2 hourly intervals
(increased to 40mcg if no response after 2 or 3 doses) vs vaginal PGE2
at 6 hourly intervals; maximum 2 vaginal doses in 12 hour period
Sample Size: 648 women
Outcomes: vaginal birth not achieved in 24 hours; caesarean birth;
uterine hyperstimulation (with and without fetal heart rate changes)
Randomisation: computer generated random number list; block sizes
between two and six (A)
Allocation Concealment: sequentially numbered, sealed opaque
envelopes (A)
Blinding: participants, caregivers and outcome assessors not blinded to
treatment allocation
Dallenbach (Dallenbach
2003)
Methods: Trial conducted at Geneva University hospital, Switzerland
between September 1999 and April 2001
Participants: women with a singleton pregnancy, cephalic presentation,
gestational age greater than 37 weeks, and Bishop score less than six;
women were excluded if non-reassuring fetal heart rate tracing,
oligohydramnios, intrauterine growth restriction, fetal malformation,
vaginal bleeding or any contraindication to prostaglandin administration
Interventions: 20mcg oral misoprostol solution at 2 hourly intervals
(increased to 40mcg) to a maximum of 10 doses vs 2mg vaginal PGE2 at
6 hourly intervals; maximum 4 doses in 24 hour period
Sample Size: 200 women
Outcomes: vaginal birth not achieved within 24 hours; caesarean birth;
uterine hyperstimulation (both with and without fetal heart rate
changes); induction to birth interval; need for augmentation of labour;
neonatal and maternal morbidity and mortality
Randomisation: computer generated random number list (A)
Allocation Concealment: sealed opaque envelopes (A)
Blinding: participants, caregivers and outcome assessors not blinded to
treatment allocation
49
Trial Identification Trial Characteristics
Shetty (Shetty 2004) Methods: Trial conducted at the Aberdeen Maternity Hospital (United
Kingdom) between October 2001 and February 2002
Participants: women with a singleton gestation in cephalic presentation,
gestational age greater than 37 weeks, and medical or obstetric
indication for induction of labour; exclusion women with prior
caesarean birth, hypersensitivity to prostaglandins, or parity > 5
Interventions: 100mcg oral misoprostol at 4 hourly intervals (to a
maximum of 5 doses) vs 3mg vaginal PGE2 at 6 hourly intervals
Sample Size: 200 women
Outcomes: vaginal birth not achieved within 24 hours; caesarean birth;
uterine hyperstimulation; induction to birth interval; need for oxytocin;
need for fetal scalp pH estimation; meconium stained liquor; infant birth
weight; admission to NICU
Randomisation: computer generated random number list (A)
Allocation Concealment: sealed opaque envelopes (A)
Blinding: participants, caregivers and outcome assessors not blinded to
treatment allocation
2.3(2) Meta-analysis
The pre-specified outcomes were well reported by Hofmeyr (Hofmeyr 2001) and
Dallenbach (Dallenbach 2003), although there was no information available about
women’s preferences and satisfaction with care.
For the primary clinical outcomes, there were no differences between oral misoprostol
and vaginal PGE2, with regards to vaginal birth not achieved within 24 hours (3 trials,
1040 participants, relative risk 1.10, 95% Confidence Intervals 0.94-1.28), uterine
hyperstimulation with associated fetal heart rate changes (5 trials, 1387 participants, RR
0.85, 95% CI 0.54-1.33) or caesarean birth (5 trials, 1387 participants, RR 0.94, 95% CI
0.77-1.16) (Table 2.3(3)i). There were no reports of serious neonatal (1 trial, 267
participants, RR not estimable) or maternal morbidity (2 trials, 962 participants, RR not
estimable) in those trials reporting these outcomes. Women administered oral
misoprostol had greater need for oxytocin augmentation (2 trials, 258 participants, RR
1.13, 95% CI 1.11-1.73), shorter induction to birth interval (4 trials, 1157 participants,
50
WMD –1.38 hours, 95% CI –2.60 to –0.15), and increased nausea reported (2 trials, 258
participants, RR 1.86, 95% CI 1.00-3.46). For the remaining secondary outcomes
reported relating to evidence of effect, maternal complications and neonatal
complications, there were no differences identified between oral misoprostol and
vaginal PGE2 (Tables 2.3(3)ii-2.3(3)iv).
Table 2.3(2)(i) Meta-analysis of primary outcomes
Outcome No.
Trials
No.
Participants
Relative Risk 95% CI
Vaginal birth >24 hours 3 1040 1.10 0.94-1.28
Hyperstimulation with FHR changes 5 1387 0.85 0.54-1.33
Caesarean section 5 1417 0.94 0.77-1.16
Serious neonatal morbidity 1 267 Not estimable
Serious maternal morbidity 2 962 Not estimable
Table 2.3(2)(ii) Meta-analysis of secondary outcomes – evidence of
effect
Outcome No.
Trials
No.
Participants
Relative Risk 95% CI
Cervix unchanged 12-24 hours 1 189 1.13 0.57- 2.24
Need for oxytocin augmentation 2 258 1.38 1.11- 1.73
Induction – birth interval* 4 1157 -1.38 -2.60- -0.15
*Weighted mean difference (interval in hours)
51
Table 2.3(2)(iii) Meta-analysis of secondary outcomes – maternal
complications
Outcome No.
Trials
No.
Participants
Relative Risk 95% CI
Hyperstimulation no FHR changes 2 862 1.04 0.66-1.65
Uterine rupture 2 891 Not estimable
Epidural analgesia 2 258 0.98 0.89-1.08
Instrumental vaginal birth 3 1092 0.90 0.68-1.20
Maternal side effects – any 2 891 1.17 0.96-1.42
Maternal side effects – nausea 2 258 1.86 1.00-3.46
Maternal side effects – vomiting 2 891 1.25 0.88-1.77
Maternal side effects – diarrhoea 2 200 0.33 0.01-8.09
Post partum haemorrhage 2 892 1.03 0.78-1.35
Maternal Death 1 692 Not estimable
Table 2.3(2)iv Meta-analysis of secondary clinical outcomes – neonatal
complications
Outcome No.
Trials
No.
Participants
Relative Risk 95% CI
Meconium Stained Liquor 3 458 1.03 0.67- 1.58
Apgar Score <7 at 5 minutes 3 949 0.71 0.34- 1.46
Admission to NICU 3 1091 0.78 0.48- 1.25
Perinatal Death 2 958 1.00 0.06-15.97
52
2.4 DISCUSSION
There are several limitations of the currently published randomised controlled trial
literature comparing oral misoprostol with vaginal prostaglandin E2, relating in
particular to the need for appropriately blinded studies, further assessment of low doses
of misoprostol, broad inclusion criteria representative of all indications for induction of
labour, and information about women’s preferences for care.
Of the 5 studies identified and included in this systematic review, only one was
described as double blind and placebo controlled (Tessier 1997). While this study
indicated that all women received both an oral and vaginal preparation, the success of
blinding was not reported. With over 80% of women and their caregivers aware of the
allocated treatment, there remains a significant potential for the introduction of bias into
these results. Inadequate allocation concealment has been shown to be associated with a
40% increase in the estimate of effect (Kunz 1998), with a similar exaggeration of
effect present in trials where there was inadequate allocation concealment or no formal
attempt at blinding (Schulz 1995).
Further randomised controlled trials comparing oral misoprostol with vaginal
prostaglandin E2 require the essential inclusion of an appropriate placebo control to
maintain blinding. This is not without difficulty, however, given appearance of
commercially available misoprostol and vaginal PGE2 gel preparations, which limits the
use of other similar appearing agents than can be used safely during pregnancy as a
placebo.
The availability of misoprostol preparations as 100 and 200mcg scored tablets has
similarly hindered the investigation of low doses of oral misoprostol in induction of
labour. Dosage variation in attempting to use 25mcg misoprostol through manual
quartering of a 100mcg tablet has been assessed (Williams 2001; Williams 2002).
While the authors concluded that an accurate low-dose form of misoprostol was
achieved (Williams 2002), it does necessitate weighing of individual tablet fragments.
53
Administration of an oral solution in which crushed misoprostol is dispersed in water
(Hofmeyr 2001; Dallenbach 2003) has allowed several investigators to assess the
efficacy of low doses (20mcg) misoprostol in the induction of labour. The
bioavailability of oral misoprostol tablets relative to an oral solution has been
investigated previously (Karim 1987), with an identical absorption profile noted to
standard tablet preparations.
In order to apply the results of any trial to the wider population concerned, the inclusion
criteria must be broad to reflect the variety of indications for which labour is induced.
Induction of labour is performed for indications where there is compromise of either
maternal or fetal condition. Trial inclusion criteria should therefore aim to include these
women, as it is important to have information regarding the use of misoprostol in these
clinical settings prior to its widespread introduction into clinical practice. The inclusion
criteria for the Tessier study (1997) were women with an “indication” for induction,
although details were not provided in the report. The trial by Hofmeyr (2001) excluded
women whose induction was performed for antepartum haemorrhage, uncontrolled
diabetes mellitus, severe pre-eclampsia, or eclampsia. The trial by Dallenbach (2003)
excluded women with a pregnancy suspected to be at risk of “fetal distress” due to non-
reassuring fetal heart rate tracing, oligohydramnios or intrauterine growth restriction.
These are all valid indications for induction of labour, and for the study results to be as
widely applicable as possible, information needs to be obtained on the use of
misoprostol in situations with suspected maternal or fetal compromise.
While misoprostol appears to be an effective agent in the induction of labour, further
information is required about its safety. With events such as uterine rupture, severe
neonatal acidosis, and maternal and neonatal death being rare, large numbers of women
will need to be induced with misoprostol before reliable clinical information regarding
these outcomes is available.
There is a lack of information in the studies to date assessing women’s preferences for
care during induction of labour. A perceived advantage of the use of oral misoprostol is
its ease and convenience for the woman and her caregivers, in particular reducing the
need for repeated vaginal examinations. The use of a vaginal placebo would necessitate
that all women involved would require vaginal examinations, a factor that may
influence their overall preferences and perception of trial participation. However,
54
information can still be obtained regarding preferences for oral or vaginal
administration of medication for future pregnancies should induction of labour be
required.
2.5 CONCLUSIONS
While oral misoprostol appears effective and safe, there have been too few trials, with
too few participants to allow study of rare but significant clinical events, such as uterine
hyperstimulation with fetal heart rate changes, meconium stained liquor, infant Apgar
score of less than seven at five minutes, and neonatal intensive care unit admission.
These outcomes have been used as indirect markers of rare and more severe outcomes
related to neonatal acidaemia. Further information regarding these outcomes is required.
Any future randomised controlled trials should address the use of low dose oral
misoprostol, with the essential inclusion of appropriate blinding of women, their
caregivers and those assessing outcome measures, to improve the reliability of
information available.
55
3. MISOPROSTOL FOR CERVICAL RIPENING AND INDUCTION OF LABOUR IN WOMEN WITH INTACT MEMBRANES AT TERM: A RANDOMISED CONTROLLED TRIAL
3.1 INTRODUCTION
The current Cochrane Systematic Review of oral misoprostol in the induction of labour
includes 13 randomised controlled trials (Alfirevic 2005), in which oral misoprostol has
been compared with placebo, intravenous oxytocin, vaginal prostaglandin E2,
intracervical prostaglandin E2, and vaginal misoprostol. Of these 13 trials, only four
were double blind and placebo controlled, one comparing oral misoprostol with placebo
(Ngai 1996); one comparing oral misoprostol with vaginal prostaglandin E2 (Tessier
1997); and two comparing oral with vaginal misoprostol (Adair 1998; Bennett 1998).
Five randomised controlled trials have been identified comparing oral misoprostol with
vaginal prostaglandin E2 gel (Tessier 1997; Gherman 2001; Hofmeyr 2001; Dallenbach
2003; Shetty 2004). When the results of these trials are combined in a meta-analysis,
there are no differences between oral misoprostol and vaginal PGE2 gel, with regards to
vaginal birth not achieved in 24 hours (3 trials, 1040 participants, RR 1.10, 95% CI
0.94-1.28), uterine hyperstimulation with associated fetal heart rate changes (5 trials,
1387 participants, RR 0.85, 95% CI 0.54-1.33), or caesarean birth (5 trials, 1387
participants, RR 0.94, 95% CI 0.77-1.16).
Only one of these trials was described as double blind and placebo controlled (Tessier
1997), and with over 80% of women and their caregivers aware of allocated treatment
there is considerable potential for the introduction of bias into these results. As
highlighted in the systematic review comparing oral misoprostol with vaginal PGE2 gel
(Chapter 2), there is a need for further randomised controlled trials to address the use of
low dose oral misoprostol, with the essential inclusion of appropriate blinding of
56
women, their caregivers and those assessing outcome measures, to improve the
reliability of information available.
3.2 STUDY AIMS & HYPOTHESES The purpose of this study was to compare the current vaginal prostaglandin E2 gel with
oral misoprostol in the induction of labour at term, in a randomised, double blind,
placebo controlled trial.
The hypotheses of the trial were that the use of oral misoprostol for the induction of
labour at term, when compared with vaginal prostaglandin E2 gel was associated with
• No difference in the number of women who remain undelivered 24 hours after
the induction process commences;
• No difference in the rate of uterine hyperstimulation associated with fetal heart
rate changes; and
• No difference in the rate of caesarean section (including those performed
primarily for fetal distress).
3.3 METHODS
3.3(1) Trial Design
A prospective randomised, double blind, placebo controlled trial comparing oral
misoprostol solution with vaginal prostaglandin E2 gel in the induction of labour at term
was conducted at the Women’s and Children’s Hospital, the Lyell McEwin Health
Service, and The Hervey Bay Hospital, between April 2001 and December 2004.
Research and ethics approval was obtained from each of the three collaborating
institutions.
Women were recruited from the antenatal clinic, antenatal wards and delivery suite of
participating institutions. Potentially eligible women presenting for induction of labour
were given the trial information sheet, counselled by a member of the study team, and
57
encouraged to discuss the study with her family. Written informed consent was then
obtained.
3.3(2) Inclusion Criteria
Women with a singleton pregnancy at a gestational age of 366 weeks or greater were
approached by a member of the study team after the decision had been made by the
attending obstetrician to induce labour. Indications for induction of labour included:
prolonged pregnancy; pre-eclampsia; hypertensive disorders; antepartum haemorrhage
(excluding placenta praevia); oligohydramnios; intra-uterine growth restriction;
gestational diabetes; and “other” indications, including social reasons.
3.3(3) Exclusion Criteria
Women with the following conditions were excluded from trial participation: active
labour (defined as regular uterine contractions, and dilatation of three centimetres or
more and full effacement of the cervix); a “favourable” cervix (defined as a modified
Bishop’s score of seven or more); a contraindication to vaginal birth; previous uterine
surgery (including prior caesarean section); maternal history of asthma, glaucoma, or
heart disease; ruptured membranes; parity of five or more; suspected cephalopelvic
disproportion; abnormal fetal lie; breech presentation; fetal distress or a non-reassuring
fetal heart rate tracing; multiple pregnancy; intrauterine infection; vasa praevia; placenta
praevia; active herpes infection; maternal illness precluding induction of labour; and
maternal renal or hepatic failure.
3.3(4) Randomisation Schedule
The randomisation schedule was generated by a non-clinical researcher using a
computer generated sequence with variable blocks and stratification for the woman’s
parity (0 and 1-4). Treatment packs were prepared by the principal investigator and the
research midwife, and labelled by a non-clinical researcher according to the generated
randomisation schedule. Opening the treatment pack was the point of randomisation.
58
3.3(5) Blinding
Treatment packs had an identical appearance, each containing six white plastic bottles.
Each bottle was labelled (oral medication 1-6) and contained an identical appearing
white powder (with either crushed misoprostol or crushed vitamin B6). The solutions
generated by dispersing the powder in water were both tasteless. Packs also contained
two sealed sterile opaque plastic bags, each with an opaque sterile syringe containing
either sterile placebo vaginal gel or sterile vaginal PGE2 gel. Both the placebo and
active vaginal gel were transferred into identical appearing syringes under sterile
conditions. All packs were sealed and a label placed across the seal to prevent
tampering or opening prior to use.
3.3(6) Treatment Allocation
When women who had given consent to trial participation were admitted to delivery
suite for induction of labour, trial entry details were confirmed. A study number was
allocated to the woman, by taking the next identically appearing, sequentially numbered
treatment pack appropriate for her parity. The study number allocated was recorded on
the trial entry form. The study treatment pack was opened, and contained either oral
misoprostol and vaginal placebo (tylose gel), or oral placebo (vitamin B6) and vaginal
prostaglandin E2 (Prostin) gel. Each pack contained a sheet detailing treatment
schedules. The treatment packs were kept at 4O Celsius (although this was not a
requirement for misoprostol).
3.3(7) Treatment Schedules
3.3(7)(i) Misoprostol Treatment Packs Each misoprostol pack contained six labelled white plastic bottles, each containing
100mcg of crushed misoprostol. This was obtained by scoring a 200mcg misoprostol
tablet and crushing the half tablet to produce a white powder. Also in the pack were two
doses of vaginal placebo (tylose) gel in sterile opaque syringes and sealed in sterile
opaque packages.
59
3.3(7)(ii) Prostaglandin E2 Treatment Packs Each placebo pack contained six labelled white plastic bottles, each containing 25mg of
crushed vitamin B6. Also in the pack were two doses of vaginal prostin gel in sterile
opaque syringes and sealed in sterile opaque packages. The prostin was transferred from
the applicators provided by the manufacturers and placed into opaque syringes identical
to the placebo gel, under sterile conditions. The packs for primigravid women contained
two doses of 2mg prostaglandin E2 gel, while packs for multiparous women contained
two doses of 1mg prostaglandin E2 gel, consistent with local hospital practices
(Government of South Australia 2005).
3.3(7)(iii) Care of all women
For all women, a preliminary fetal cardiotocogram (CTG) was recorded for 20 minutes,
and had to be within normal limits for the study preparation to be given. A vaginal
examination was performed and the initial Bishop’s score recorded. The intravaginal gel
was then given (either prostaglandin E2 or placebo gel). The CTG was continued for a
period of 20 minutes after the trial medication had been administered.
The oral solution was made up immediately prior to administration of the current
required dose by the primary care midwife. The powder (either misoprostol or vitamin
B6) from the plastic bottle was transferred to a brown glass bottle of 100mL capacity. A
total of 100mL of water was added to the bottle, the lid replaced, and the contents
shaken to mix the powder and water. This produced a solution of 1mcg/mL of
misoprostol in the active solution. A 20mL aliquot of solution (to produce a dose of
20mcg misoprostol solution in the misoprostol group) was then taken and administered
orally to the woman. The remaining 80mL of solution was discarded. This procedure
was repeated at two hourly intervals, with a CTG being obtained for 20 minutes prior
and following each oral dose.
The oral solution was administered at two hourly intervals to a maximum of 6 doses
over a 12-hour period. The vaginal gel (2mg dose for nulliparous women and 1mg for
multiparous women in the prostaglandin E2 group and tylose gel for women in the
misoprostol group) was administered at six hourly intervals to a maximum of 2 doses
over a 12-hour period. The second dose of vaginal gel if required (2mg dose for
nulliparous women and 1mg for multiparous women in the prostaglandin E2 group and
60
tylose gel for women in the misoprostol group), was given concurrently with the fourth
oral solution if this was required. All women underwent a vaginal examination six hours
after the administration of the first dose of vaginal PGE2 gel, and six hours after the
administration of the second dose of vaginal PGE2 gel if this was required. All care
provided to women was according to local hospital guidelines, with the exception of the
administration of trial medications as described.
All trial medication was ceased once the woman’s cervix was suitable for artificial
rupture of the membranes (ARM), following spontaneous rupture of the membranes
(SROM), or in the presence of three to four regular uterine contractions in a 10-minute
period.
Following ARM, SROM, the onset of labour, or completion of all study medications,
women were managed according to the usual delivery suite protocols, including
administration of known prostaglandin E2 gel if the cervix remained unfavourable, or
the use of oxytocin infusion if required. The further administration of vaginal PGE2 gel
was at the discretion of the consultant obstetrician on call for delivery suite if the
woman’s cervix remained unfavourable.
3.3(8) Study Outcome Measures
3.3(8)(i) Primary Study Outcomes
The primary study outcomes were consistent with those in the Cochrane generic
protocol relating to induction of labour (Hofmeyr 2005a), and were
• vaginal birth not achieved within 24 hours,
• uterine hyperstimulation with associated fetal heart rate changes,
• caesarean section (all), and
• caesarean section for fetal distress.
Uterine hyperstimulation was defined as uterine tachysystole (with five or more
contractions in a 10 minute period for two consecutive 10 minute periods) or uterine
hypertonus (a uterine contraction lasting for more than two minutes) (Curtis 1987). The
fetal heart rate changes that were recorded as abnormal included persistent decelerations
(early, late or variable decelerations), fetal tachycardia (fetal heart rate greater than 160
61
beats per minute), fetal bradycardia (fetal heart rate less than 100 beats per minute), or
reduced short term variability (less than five beats per minute) (RANZCOG 2001;
RCOG 2001). The presence of uterine hyperstimulation in the presence of fetal heart
rate changes was managed with intravenous salbutamol according to delivery suite
protocols. Each induction of labour CTG was reviewed by a single investigator to
maintain consistency in interpretation while blinded to the treatment allocated.
3.3(8)(ii) Secondary Study Outcomes
Secondary study outcomes recorded related to evidence of effect, neonatal
complications and maternal complications as described in the Cochrane generic
protocol relating to methods of induction of labour (Table 3.3(6)(ii)) (Hofmeyr 2005a).
Secondary outcome
Evidence of Effect Cervix unfavourable or unchanged after 24 hours
Further doses of known PGE2 gel
Need for oxytocin infusion
Induction to birth interval
Labour and Birth Complications Uterine hyperstimulation without fetal heart rate changes (defined as uterine
tachysystole – five or more contractions in a ten minute period for two or more
consecutive ten minute periods; or uterine hypertonus – a uterine contraction lasting for
more than two minutes) (Curtis 1987)
Uterine rupture (defined as full thickness separation of the uterine muscle discovered at
laparotomy; incidental scar dehiscence is not included)
Need for analgesia (any analgesia, epidural analgesia)
Meconium Stained Liquor
Instrumental vaginal birth
Postpartum haemorrhage (greater than 600mL, greater than 1000mL, need for blood
transfusion)
Neonatal Complications Birth weight less than 2.5kg
Apgar score of less than 7 at five minutes
Cord pH less than 7.18
Admission to neonatal intensive care unit
Neonatal death (defined as death of a live born infant within 28 days of birth)
Neonatal encephalopathy
Maternal Complications Maternal side effects (nausea, vomiting, diarrhoea, flushing)
Serious maternal complications (admission to intensive care unit, hyperpyrexia, coma)
Maternal death
Table 3.3(8)(ii) Secondary outcomes
62
3.3(9) Data Collection
Data forms were completed by the midwife caring for the woman, with information
confirmed and checked by the principal investigator or research midwife prior to the
woman being discharged from hospital. All data were then entered into a database
created in Access ’97 (Microsoft Corporation 1997) by the principal investigator.
3.3(10) Statistical Analysis
Data were analysed on an intention-to-treat basis and blind to the allocated treatment
using the SAS Version 9.1 statistical software programme (SAS Institute Incorporated
2003). Baseline data were examined by treatment group to ensure comparability for
prognostic factors, with correction for imbalances using log binomial regression
techniques. The primary and secondary outcomes were compared using χ2 tests or
Fisher’s Exact Test, with calculation of relative risks (RR) with 95% Confidence
Intervals (CI) for dichotomous data. Normally distributed continuous data were
compared using the Student’s T-test, and skewed data using non-parametric tests
(Wilcoxon Rank Sum). Pre-specified subgroup analyses were planned to assess the
effect of maternal parity (nulliparous versus multiparous) and initial Bishop’s score at
commencing induction (Bishop’s score 0-3 versus Bishop’s score 4-6) on treatment
effect. A p value of less than 0.05 was considered statistically significant.
3.3(11) Sample Size
Using information from the Cochrane review of oral misoprostol for induction of labour
at term (Alfirevic 2005), and figures generated by the Women’s and Children’s Hospital
Clinical Information Service, a sample size of 738 women was calculated to give 85%
power to detect a 50% difference in the number of women undelivered after 24 hours
from 20% in the vaginal prostaglandin group to 30% in the misoprostol group (p<0.05);
a 32% difference in caesarean section from 28% in the vaginal prostaglandin group to
19% in the misoprostol group; and a 72% difference in the rate of hyperstimulation
from 2% in the vaginal prostaglandin group to 6% in the misoprostol group (p<0.05;
power 80%).
63
3.4 RESULTS
3.4(1) Baseline Characteristics
A total of 1319 eligible women were approached for trial participation by a clinical
researcher at the time of booking the induction of labour, of whom 939 (71.2%)
provided written consent to participate (Figure 3.4(1)). Of women who gave consent,
199 (21.2%) entered labour spontaneously prior to the date of booked induction of
labour, and 741(78.8%) were admitted for induction of labour and randomised into the
trial, 365 women to the oral misoprostol group, and 376 to the vaginal PGE2 group. The
treatment allocated at randomisation was received by 740 (99.9%) of women, with one
woman randomised to the vaginal prostaglandin E2 group receiving known
prostaglandin E2 gel. Outcome data were available on all women to the time of
discharge from hospital (Figure 3.4(1)).
Figure 3.4(1) Trial Flow Chart
Spontaneous onset labourprior to scheduled induction
199 (21.2%)
Outcome Data Available365 (100%)
Allocated Treatment Received365 (100%)
Misoprostol365 women
Outcome Data Available376 (100%)
Allocated Treatment Received375 (99.7%)
Vaginal PGE2376 women
Eligible Women Randomised741 (78.8%)
Eligible Women Consenting939 (71.2%)
Eligible Women Declined380 (28.8%)
Eligible Women Approached1319
64
Of the women participating in the trial, 59% were in their first ongoing pregnancy, and
97% were of caucasian background. The most common indication for induction of
labour was post dates, accounting for 48% of all inductions, followed by hypertensive
conditions (including pre-eclampsia), accounting for 23% of all inductions, and social
indications (including maternal discomfort and maternal request), accounting for 14%
of all inductions performed.
Baseline characteristics were comparable between the two treatment groups, including
maternal age, parity, booking weight, smoking during pregnancy, gestational age, and
reason for induction of labour. However, there were differences in the number of
women with an initial Bishop’s score of 0-3 between the two treatment groups, and
adjustments for this imbalance were made in the analyses using log binomial regression
techniques, with the exception of those analyses exploring the effect of Bishop’s score
(Table 3.4(1)).
Table 3.4(1) Comparison of baseline variables at trial entry
Misoprostol Group
N=365 % PGE2 Group N=376 %
Age (years)* 27.9 5.6 28.0 5.6 Nulliparous 213 58.4 221 58.8 Caucasian 355 97.3 362 96.3 Public patient 362 99.2 376 100.0 Indication for induction of labour
- post dates - pre-eclampsia - hypertension - intra-uterine growth restriction - abnormal glucose tolerance - social - other
181 49.6
30 8.2 49 13.4 24 6.6
29 8.0 55 15.1 21 5.8
175 46.5
37 9.8 55 14.6 32 8.5 46 12.2
46 12.2 25 6.6
Initial Bishop’s score - Bishop’s score 0-3 - Bishop’s score 4-6
246 67.4 119 32.6
214 56.9 162 43.1
Mean Gestational Age (weeks)* 40.6 2.0 40.4 2.1 Height (m)* 165.1 5.8 165.0 6.6 Weight at booking (kg)# 72.0 48-96 75.0 49-101 Body Mass Index >30 (kg/m2) at booking 94 34.0 98 33.1 Smoking at booking 84 23.0 86 22.9
Figures are numbers and percentages.
* = mean and standard deviation
# = median and interquartile range
65
3.4(2) Primary Outcomes
There were no statistically significant differences identified between oral misoprostol
and vaginal PGE2 gel for vaginal birth not achieved in 24 hours (Misoprostol 168/365
(46.0%) versus PGE2 155/376 (41.2%); RR 1.12 95% CI 0.95-1.32; p=0.134), caesarean
section (Misoprostol 83/365 (22.7%) versus PGE2 100/376 (26.6%); RR 0.82 95% CI
0.64-1.06; p=0.127), caesarean section performed for fetal distress (Misoprostol 32/365
(8.8%) versus PGE2 35/376 (9.3%); RR 0.91 95% CI 0.57-1.44; p=0.679), or uterine
hyperstimulation with associated fetal heart rate changes (Misoprostol 3/365 (0.8%)
versus PGE2 6/376 1.6%); RR 0.55 95% CI 0.14-2.21; p=0.401) (Table 3.4(2)).
Table 3.4(2) Primary Outcomes
Misoprostol
Group
PGE2 Group Treatment Effect
RR 95% CI
P
value
All women
- Vaginal Birth not achieved 24 hours
- Uterine HSS with FHR changes
- Caesarean section - all
- Caesarean section - fetal distress
N=365 %
168 46.0
3 0.8
83 22.7
32 8.8
N=376 %
155 41.2
6 1.6
100 26.6
35 9.3
1.12 0.95- 1.32
0.55 0.14- 2.21
0.82 0.64- 1.06
0.91 0.57- 1.44
0.134
0.401
0.127
0.679
Statistically significant results (p<0.05) in bold text.
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect.
HSS = hyperstimulation syndrome
FHR = fetal heart rate
66
3.4(3) Secondary Outcomes – Evidence of Effect
Women in the oral misoprostol group were significantly more likely to have a Bishop’s
score of less than seven 24 hours after commencing the induction (Misoprostol 57/365
(15.6%) versus PGE2 39/376 (10.4%); RR 1.51 95% CI 1.03-2.20; p=0.031), were more
likely to require further doses of known vaginal PGE2 gel (Misoprostol 70/365 (19.2%)
versus PGE2 47/376 (12.5%); RR 1.51 95% CI 1.01-1.97; p=0.043), and were more
likely to require an oxytocin infusion during labour (Misoprostol 203/365 (55.6%)
versus PGE2 179/376 (47.6%); RR 1.17 95% CI 1.01-1.34; p=0.034) (Table 3.4(3)). For
every 23 women treated with misoprostol, one woman requires further doses of vaginal
PGE2 gel (NNTH 23; 95% CI 12-4021), and for every 13 women treated with
misoprostol, one woman requires oxytocin infusion during labour (NNTH 13; 95% CI
7-162). Women administered oral misoprostol had a longer induction to birth interval
when compared with women administered vaginal PGE2 gel (Misoprostol median
interval 21.2 hours, interquartile range 8.6-33.8 versus PGE2 median interval 18.4
hours, interquartile range 6.3-30.5; p<0.001).
Table 3.4(3) Secondary Outcomes – Evidence of Effect
Misoprostol Group PGE2 Group Treatment
Effect
RR 95% CI
P
value
All women
- Bishop’s Score <7 after 24 hours
- Further doses of known PGE2
- Oxytocin infusion
- Induction to birth interval*
N=365 %
57 15.6
70 19.2
203 55.6
21.2 8.6-33.8
N=376 %
39 10.4
47 12.5
179 47.6
18.4 6.3-30.5
1.51 1.03-2.20
1.41 1.01-1.97
1.17 1.01-1.34
0.031
0.043
0.034
<0.001
Statistically significant results (p<0.05) in bold text.
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect.
*Median and interquartile range (interval in hours); Wilcoxon Rank Sum Test
PGE2 = vaginal prostaglandin E2 gel
67
3.4(4) Secondary Outcomes – Labour and Birth Complications
There were no differences in the mean length of labour for women receiving oral
misoprostol compared with women receiving vaginal PGE2 gel (Misoprostol mean
interval 7.5 hours, standard deviation 4.1 versus PGE2 mean interval 6.9 hours, standard
deviation 4.0; p=0.073). Women randomised to the oral misoprostol group were
significantly less likely to have uterine hyperstimulation without associated fetal heart
rate changes (Misoprostol 4/365 (1.1%) versus PGE2 17/376 (4.5%); RR 0.23 95% CI
0.08-0.69; p=0.009)(Table 3.4(4)).
Women in the oral misoprostol group were more likely to require analgesia during
labour (Misoprostol 351/365 (96.2%) versus PGE2 347/376 92.3%); RR 1.04 95% CI
1.00-1.08; p=0.035) when compared with women in the PGE2 group (Table 3.4(4)).
However, there were no statistically significant differences between women in the oral
misoprostol group and those in the vaginal PGE2 gel group in the use of epidural
analgesia (Misoprostol 243/365 (66.6%) versus PGE2 229/376 (60.9%); RR 1.08 95%
CI 0.97-1.21; p=0.149), the presence of meconium stained liquor during labour
(Misoprostol 59/365 (16.2%) versus PGE2 52/376 (13.8%); RR 1.14 95% CI 0.81-1.61;
p=0.465), instrumental vaginal birth (Misoprostol 57/365 (15.6%) versus PGE2 77/376
(20.5%); RR 1.06 95% CI 0.77-1.46; p=0.712), blood loss greater than 600mL
(Misoprostol 57/365 (15.6%) versus PGE2 77/376 (20.5%); RR 0.76 95% CI 0.55-1.04;
p=0.081), blood loss greater than 1000mL (Misoprostol 17/365 (4.7%) versus PGE2
20/376 (5.3%); RR 0.86 95% CI 0.46-1.63; p=0.646), or need for blood transfusion
(Misoprostol 8/365 (2.2%) versus PGE2 9/376 (2.4%); RR 0.96 95% CI 0.37-2.47;
p=0.927).
68
Table 3.4(4) Secondary Outcomes – Labour & Birth Complications
Misoprostol Group
PGE2 Group Treatment Effect RR 95% CI
P value
All women - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=365 % 4 1.1 0 0.0 351 96.2 243 66.6 59 16.2 7.5 4.1 65 17.8 57 15.6 17 4.7 8 2.2
N=376 % 17 4.5 0 0.0 347 92.3 229 60.9 52 13.8 6.9 4.0 63 16.8 77 20.5 20 5.3 9 2.4
0.23 0.08-0.69 Not estimable 1.04 1.00-1.08 1.08 0.97-1.21 1.14 0.81-1.61 1.06 0.77-1.46 0.76 0.55-1.04 0.86 0.46-1.63 0.96 0.37-2.47
0.009 0.035 0.149 0.465 0.073 0.712 0.081 0.646 0.927
Statistically significant results (p<0.05) in bold text.
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect.
* Mean and standard deviation (interval in hours); Student’s T-Test
HSS = hyperstimulation syndrome
FHR = fetal heart rate
3.4(5) Secondary Outcomes - Neonatal Complications
Infant birth weight did not differ significantly between the oral misoprostol group and
the vaginal PGE2 gel group (Misoprostol 3533g + 534 versus PGE2 3540g + 490;
p=0.840). Similarly, there were no significant differences between the oral misoprostol
group and the vaginal PGE2 group for the number of infants with birth weight less than
2500g (Misoprostol 15/365 (4.1%) versus PGE2 11/376 (2.9%); RR 1.30 95% CI 0.60-
2.79; p=0.505), Apgar score of less than seven at five minutes of age (Misoprostol
2/365 (0.6%) versus PGE2 5/376 (1.3%); RR 0.42 95% CI 0.08-2.15; p=0.297), cord pH
less than 7.18 (Misoprostol 10/365 (7.6%) versus PGE2 19/376 (11.6%); RR 0.62 95%
CI 0.30-1.29; p=0.205), or admission to NICU (Misoprostol 5/365 (1.4%) versus PGE2
2/376 (0.5%); RR 2.66 95% CI 0.52-13.75; p=0.242) (Table 3.4(5)). Of infants admitted
to the neonatal intensive care unit, two were for major undiagnosed cardiac defects (one
in the misoprostol group and one in the PGE2 group), three required intubation (two in
the misoprostol group and one in the PGE2 group), one required blood transfusion
69
following intrapartum feto-maternal haemorrhage (misoprostol group) and one required
treatment for pronounced hypoglycaemia (misoprostol group).
Table 3.4(5) Secondary Outcomes - Neonatal Complications
Misoprostol Group
PGE2 Group Treatment Effect RR 95%CI
P value
All infants - Birth-weight <2.5kg - Apgar <7 @ 5 minutes - Cord pH <7.18 - NICU admission - Neonatal encephalopathy - Neonatal death*
N=365 % 15 4.1 2 0.6 10 7.6 5 1.4 0 0.0 0 0.0
N=376 % 11 2.9 5 1.3 19 11.6 2 0.5 0 0.0 0 0.0
1.30 0.60- 2.79 0.42 0.08- 2.15 0.62 0.30- 1.29 2.66 0.52-13.75 Not estimable Not estimable
0.505 0.297 0.205 0.242
Statistically significant results (p<0.05) in bold text. Figures are numbers and
percentages with relative risk (RR) and 95% Confidence Intervals (CI) as treatment
effect.
*Neonatal Death = death of a live-born infant within 28 days of birth
NICU = neonatal intensive care unit
3.4(6) Secondary Outcomes - Maternal Complications
In considering maternal experience of any side effects, there were no statistically
significant differences between the oral misoprostol and vaginal PGE2 gel (Misoprostol
76/365 (20.8%) versus PGE2 99/376 (26.3%); RR 0.78 95% CI 0.60-1.01; p=0.063).
Similarly, there were no differences in the number of women experiencing nausea
(Misoprostol 20/365 (5.5%) versus PGE2 30/376 (8.0%); RR 0.68 95% CI 0.39-1.19;
p=0.175), vomiting (Misoprostol 4/365 (1.1%) versus PGE2 10/376 (2.7%); RR 0.43
95% CI 0.14-1.37; p=0.154), diarrhoea (Misoprostol 5/365 (1.4%) versus PGE2 9/376
(2.4%); RR 0.53 95% CI 0.18-1.57; p=0.250) or flushing (Misoprostol 6/365 (1.6%)
versus PGE2 4/376 (1.1%); RR 1.43 95% CI 0.41-5.05; p=0.578) (Table 3.4(6)). No
women in either group were admitted to intensive care, suffered hyperpyrexia or coma.
There were no maternal deaths.
70
Table 3.4(6) Secondary Outcomes - Maternal Complications
Misoprostol Group
PGE2 Group Treatment Effect RR 95% CI
P value
All women - Any side effect - Nausea - Vomiting - Diarrhoea - Flushing - Intensive care unit admission - Hyperpyrexia - Coma - Maternal death
N=365 % 76 20.8 20 5.5 4 1.1 5 1.4 6 1.6 0 0.0 0 0.0 0 0.0 0 0.0
N=376 % 99 26.3 30 8.0 10 2.7 9 2.4 4 1.1 0 0.0 0 0.0 0 0.0 0 0.0
0.78 0.60-1.01 0.68 0.39-1.19 0.43 0.14-1.37 0.53 0.18-1.57 1.43 0.41-5.05 Not estimable Not estimable Not estimable Not estimable
0.063 0.175 0.154 0.250 0.578
Statistically significant results (p<0.05) in bold text.
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect.
3.4(7) Pre-specified Secondary Analyses – Effect of Maternal Parity
and Bishop’s Score at Trial Entry
3.4(7)(i) Distribution of maternal parity and initial Bishop’s score
Of the 365 women randomised to the misoprostol group, 213 (58.4%) were nulliparous,
of whom 143 (67.1%) had an initial Bishop’s score of 0-3, and 70 (32.9%) an initial
Bishop’s score of 4-6. There were 152 (41.6%) multiparous women in the misoprostol
group, of whom 103 (67.8%) had an initial Bishop’s score of 0-3, and 49 (32.3%) an
initial Bishop’s score of 4-6 (Table 3.4(7)(i)).
Of the 376 women randomised to the vaginal PGE2 group, 221 (58.8%) were
nulliparous, of whom 126 (57.0%) had an initial Bishop’s score of 0-3, and 95 (43.0%)
an initial Bishop’s score of 4-6. There were 155 (41.2%) multiparous women in the
vaginal PGE2 group, of whom 88 (56.8%) had an initial Bishop’s score of 0-3, and 67
(43.2%) an initial Bishop’s score of 4-6 (Table 3.4(7)(i)).
71
Table 3.4(7)(i) Distribution of maternal parity and initial Bishop’s score
Misoprostol Group
N=365 % PGE2 Group N=376 %
Bishop’s Score - Bishop’s score 0-3 - Bishop’s score 4-6
246 67.4 119 32.6
214 56.9 162 43.1
Nulliparous women - Bishop’s score 0-3 - Bishop’s score 4-6
213 58.4 143 67.1 70 32.9
376 58.8 126 57.0 95 43.0
Multiparous women - Bishop’s score 0-3 - Bishop’s score 4-6
152 41.6 103 67.8 49 32.3
155 41.2 88 56.8 67 43.2
Figures are numbers and percentages
3.4(7)(ii) Effect of parity and initial Bishop’s score on primary trial outcomes
For the outcomes of vaginal birth not achieved within 24 hours, uterine
hyperstimulation with associated fetal heart rate changes, caesarean section and
caesarean section for fetal distress, there were no statistically significant differences
identified on the basis of maternal parity (nulliparous versus multiparous) or the
Bishop’s score at trial entry (Bishop’s score 0-3 versus Bishop’s score 4-6) (Table
3.4(7)(ii)). The magnitude of treatment effect was similar across all of the pre-specified
subgroups.
72
Table 3.4(7)(ii) Secondary Analysis - Primary Outcomes
Misoprostol Group PGE2 Group Treatment Effect RR 95% CI
P value
All women - Vaginal Birth not achieved in 24 hours - Uterine HSS with FHR changes - Caesarean section - all - Caesarean section - fetal distress
N=365 % 168 46.0 3 0.8 83 22.7 32 8.8
N=376 % 155 41.2 6 1.6 100 26.6 35 9.3
1.12 0.95- 1.32 0.55 0.14- 2.21 0.82 0.64- 1.06 0.91 0.57- 1.44
0.134 0.401 0.127 0.679
Bishop’s score 0-3 - Vaginal Birth not achieved in 24 hours - Caesarean section – all - Caesarean section – fetal distress
N=246 % 127 51.6 61 24.8 24 9.8
N=214 % 104 48.6 67 31.3 23 10.8
1.06 0.88-1.28 0.79 0.59-1.06 0.91 0.53-1.56
0.210 0.120 0.726
Bishop’s score 4-6 - Vaginal Birth not achieved in 24 hours - Caesarean section – all - Caesarean section – fetal distress
N=119 % 41 34.5 22 18.5 8 6.7
N=162 % 51 31.5 33 20.4 12 7.4
1.09 0.78-1.53 0.91 0.56-1.47 0.91 0.38-2.15
0.234 0.694 0.825
Nulliparous women - Vaginal Birth not achieved in 24 hours - Caesarean section - all - Caesarean section – fetal distress
N=213 % 133 62.4 67 31.5 22 10.3
N=221 % 119 53.8 81 36.7 28 12.7
1.16 0.99- 1.36 0.83 0.64- 1.07 0.79 0.47- 1.33
0.157 0.155 0.375
Nulliparous women, BS 0-3 - Vaginal Birth not achieved in 24 hours - Caesarean section - all - Caesarean section – fetal distress
N=143 % 101 70.6 49 34.3 17 11.9
N=126 % 80 63.5 53 42.1 18 14.3
1.11 0.94-1.32 0.81 0.60- 1.11 0.83 0.45- 1.54
0.145 0.188 0.600
Nulliparous women, BS 4-6 - Vaginal Birth not achieved in 24 hours - Caesarean section - all - Caesarean section – fetal distress
N= 70 % 32 45.7 18 25.7 5 7.1
N= 95 % 39 41.1 28 29.5 10 10.5
1.11 0.78- 1.58 0.87 0.53- 1.45 0.68 0.24- 1.90
0.136 0.595 0.455
Multiparous women - Vaginal Birth not achieved in 24 hours - Caesarean section – all - Caesarean section – fetal distress
N=152 % 35 23.0 16 10.5 10 6.6
N=155 % 36 23.2 19 12.3 7 4.5
0.99 0.66- 1.49 0.82 0.44- 1.54 1.40 0.55- 3.58
0.790 0.542 0.485
Multiparous women, BS 0-3 - Vaginal Birth not achieved in 24 hours - Caesarean section – all - Caesarean section – fetal distress
N=103 % 26 25.2 12 11.7 7 6.8
N= 88 % 24 27.3 14 15.9 5 5.7
0.93 0.57- 1.49 0.73 0.36- 1.50 1.20 0.39- 3.64
0.643 0.392 0.752
Multiparous women, BS 4-6 - Vaginal Birth not achieved in 24 hours - Caesarean section – all - Caesarean section – fetal distress
N= 49 % 9 18.4 4 8.2 3 6.1
N= 67 % 12 17.9 5 7.5 2 3.0
1.03 0.47- 2.24 1.09 0.31- 3.86 2.05 0.36-11.81
0.966 0.889 0.411
Statistically significant results (p<0.05) in bold text.
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect.
BS = Bishop’s Score; HSS = hyperstimulation syndrome; FHR = fetal heart rate
73
3.4(7)(iii) Secondary Analysis – Secondary Outcomes of Evidence of Effect
Nulliparous women administered misoprostol, when compared with those administered
vaginal PGE2 gel, were significantly more likely to have a Bishop’s score of less than
seven 24 hours after the induction commenced (Misoprostol 46/213 (21.6%) versus
PGE2 26/221 (11.8%); RR 1.69 95% CI 1.09-2.64; p=0.024), and to require further
doses of vaginal PGE2 gel (Misoprostol 57/213 (26.8%) versus PGE2 27/221 (12.2%);
RR 2.15 95% CI 1.35-3.12; p<0.001) (Table 3.4(7)(iii)). These effects were confined to
those nulliparous women with a Bishop’s score of 0-3 at the commencement of the
induction process (Bishop’s score of less than seven 24 hours after induction
commenced (Misoprostol 39/143 (27.3%) versus PGE2 20/126 (15.9%); RR 1.72 95%
CI 1.06-2.78; p=0.022), and need for further doses of vaginal PGE2 gel (Misoprostol
48/143 (33.6%) versus PGE2 19/126 (15.1%); RR 2.23 95% CI 1.39-3.58; p<0.001).
Women administered misoprostol had a longer induction to birth interval when
compared with women in the vaginal PGE2 gel group, an effect apparent in women with
an initial Bishop’s score of 0-3 (Misoprostol median interval 22.3 hours, interquartile
range 13.0 versus PGE2 median interval 20.3 hours, interquartile range 12.3; p=0.039),
nulliparous women (Misoprostol median interval 24.5 hours, interquartile range 11.1
versus PGE2 median interval 20.9 hours, interquartile range 12.2; p<0.001), and
nulliparous women with an initial Bishop’s score of 0-3 (Misoprostol median interval
25.8 hours, interquartile range 11.3 versus PGE2 median interval 22.8 hours,
interquartile range 12.9; p<0.001).
The increased need for oxytocin infusion during labour was confined to multiparous
women administered oral misoprostol (Misoprostol 64/152 (42.1%) versus PGE2 48/155
(42.1%); RR 1.36 95% CI 1.00-1.83; p=0.049), regardless of the woman’s cervical
score at the start of the induction. However, multiparous women with an initial Bishop’s
score of 0-3 in the misoprostol group were less likely to require further doses of vaginal
PGE2 gel (Misoprostol 10/103 (9.7%) versus PGE2 18/88 (20.5%); RR 0.47 95% CI
0.23-0.97; p=0.036).
74
Table 3.4(7)(iii) Secondary Analysis – Evidence of Effect
Misoprostol Group PGE2 Group Treatment Effect RR 95%CI
P value
All women - Bishop’s Score <7 after 24 hours - Further doses of known PGE2- Oxytocin infusion - Induction to birth interval*
N=365 % 57 15.6 70 19.2 203 55.6 21.2 8.6-33.7
N=376 % 39 10.4 47 12.5 179 47.6 18.4 6.3-30.5
1.51 1.03- 2.20 1.41 1.01- 1.97 1.17 1.01- 1.34
0.031 0.043 0.034 <0.001
Bishop’s score 0-3 - Bishop’s score <7 after 24 hours - Further doses of known PGE2- Oxytocin infusion - Induction to birth interval*
N=246 % 48 19.5 58 23.6 137 55.7 22.3 9.3-35.3
N=214 % 31 14.5 37 17.3 104 48.6 20.3 8.0-32.6
1.09 0.78-1.52 1.36 0.94-1.97 1.15 0.96-1.37
0.606 0.097 0.129 0.039
Bishop’s score 4-6 - Bishop’s score <7 after 24 hours - Further doses of known PGE2
- Oxytocin infusion - Induction to birth interval*
N=119 % 9 7.6 12 10.1 66 55.5 19.3 9.0-29.6
N=162 % 8 4.9 10 6.2 75 46.3 17.3 7.4-27.2
1.02 0.45-2.29 1.63 0.73-3.65 1.20 0.95-1.51
0.963 0.228 0.129 0.060
Nulliparous women - Bishop’s Score <7 after 24 hours - Further doses of known PGE2
- Oxytocin infusion - Induction to birth interval*
N=213 % 46 21.6 57 26.8 139 65.3 24.5 13.4-35.6
N=221 % 26 11.8 27 12.2 131 59.3 20.9 8.7-33.1
1.69 1.09- 2.64 2.05 1.35- 3.12 1.10 0.95- 1.27
0.024 <0.001 0.220 <0.001
Nulliparous women, BS 0-3 - Bishop’s Score <7 after 24 hours - Further doses of known PGE2
- Oxytocin infusion - Induction to birth interval*
N=143 % 39 27.3 48 33.6 96 67.1 25.8 14.5-37.1
N=126 % 20 15.9 19 15.1 77 61.1 22.8 9.9-35.7
1.72 1.06- 2.78 2.23 1.39- 3.58 1.09 0.92- 1.32
0.022 <0.001 0.304 <0.001
Nulliparous women, BS 4-6 - Bishop’s Score <7 after 24 hours - Further doses of known PGE2- Oxytocin infusion - Induction to birth interval*
N= 70 % 7 10.0 9 12.9 43 61.4 21.7 11.5-31.9
N= 95 % 6 6.3 8 8.4 54 56.8 18.6 7.6-29.6
1.58 0.56- 4.51 1.53 0.62- 3.76 1.08 0.84- 1.40
0.9658 0.3542 0.5542 0.0258
Multiparous women - Bishop’s Score <7 after 24 hours - Further doses of known PGE2- Oxytocin infusion - Induction to birth interval*
N=152 % 11 7.2 13 8.6 64 42.1 15.3 5.0-25.6
N=155 % 13 8.4 20 12.9 48 31.0 16.6 6.2-27.0
0.86 0.40- 1.87 0.59 0.30- 1.14 1.36 1.00- 1.83
0.464 0.115 0.049 0.232
Multiparous women, BS 0-3 - Bishop’s Score <7 after 24 hours - Further doses of known PGE2- Oxytocin infusion - Induction to birth interval*
N=103 % 9 8.7 10 9.7 41 39.8 16.4 5.8-27.0
N= 88 % 11 12.5 18 20.5 27 30.7 17.8 5.7-29.9
0.70 0.30- 1.61 0.47 0.23- 0.97 1.29 0.88- 1.92
0.234 0.036 0.189 0.466
Multiparous women, BS 4-6 - Bishop’s Score <7 after 24 hours - Further doses of known PGE2- Oxytocin infusion - Induction to birth interval*
N= 49 % 2 4.1 3 6.1 23 46.9 14.9 5.0-24.8
N= 67 % 2 3.0 2 3.0 21 31.3 14.8 6.1-23.5
1.37 0.20- 9.37 2.05 0.36-11.81 1.50 0.94- 2.38
0.876 0.411 0.087 0.909
Statistically significant results (p<0.05) in bold text.
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect.
* Median and interquartile range (interval in hours); Wilcoxon Rank Sum Test
BS = Bishop’s Score
PGE2 = vaginal prostaglandin E2 gel
75
3.4(7)(iv) Secondary Analysis –Labour & Birth Complications
Nulliparous women randomised to the oral misoprostol group were significantly less
likely to have uterine hyperstimulation without associated fetal heart rate changes when
compared with women randomised to the PGE2 group (Misoprostol 3/213 (1.4%) versus
PGE2 15/221 (6.8%); RR 0.20 95% CI 0.06-0.69; p=0.011), as were those women with
an initial Bishop’s score of 0-3 (Misoprostol 3/246 (1.2%) versus PGE2 11/214 (5.1%);
RR 0.24 95% CI 0.07-0.84; p=0.015) (Table 3.4(7)(iv)). This effect was greatest for
nulliparous women with a Bishop’s score of 0-3 (Misoprostol 2/143 (1.4%) versus
PGE2 9/126 (7.1%); RR 0.20 95% CI 0.04-0.89; p=0.018). Multiparous women in the
misoprostol group were less likely to require an instrumental vaginal birth when
compared with women in the vaginal PGE2 group (Misoprostol 7/152 (4.6%) versus
PGE2 17/155 (11.0%); RR 0.42 95% CI 0.18-0.98; p=0.046). The mean length of labour
did not differ significantly between women administered oral misoprostol and those
administered vaginal PGE2 gel, with no interaction on the basis of maternal parity or
initial Bishop’s score.
Table 3.4(7)(iv) Secondary Analysis – Labour & Birth Complications
Misoprostol Group PGE2 Group Treatment Effect RR 95% CI
P value
All women - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=365 % 4 1.1 0 0.0 351 96.2 243 66.6 59 16.2 7.5 4.1 65 17.8 57 15.6 17 4.7 8 2.2
N=376 % 17 4.5 0 0.0 347 92.3 229 60.9 52 13.8 6.9 4.0 63 16.8 77 20.5 20 5.3 9 2.4
0.23 0.08-0.69 Not estimable 1.04 1.00-1.08 1.08 0.97-1.21 1.14 0.81-1.61 1.06 0.77-1.46 0.76 0.55-1.04 0.86 0.46-1.63 0.96 0.37-2.47
0.009 0.035 0.149 0.465 0.073 0.712 0.081 0.646 0.927
Bishop’s Score 0-3 - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=246 % 3 1.2 0 0.0 236 95.9 163 66.3 43 17.5 7.5 4.1 14 17.9 37 15.0 10 4.1 3 1.2
N=214 % 11 5.1 0 0.0 200 93.5 137 64.0 33 15.4 7.0 3.8 36 16.8 47 22.0 14 6.5 6 2.8
0.24 0.07-0.84 Not estimable 1.03 0.98-1.07 1.04 0.90-1.18 1.13 0.75-1.72 1.06 0.71-1.59 0.68 0.46-1.01 0.62 0.28-1.37 0.44 0.11-1.72
0.015 0.233 0.615 0.553 0.266 0.764 0.055 0.233 0.221
76
Misoprostol Group PGE2 Group Treatment Effect RR 95% CI
P value
Bishop’s Score 4-6 - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=119 % 1 0.8 0 0.0 115 96.6 80 67.2 16 13.5 7.5 3.9 21 17.7 20 16.8 7 5.9 5 4.2
N=162 % 6 3.7 0 0.0 147 90.7 92 56.8 19 11.7 6.7 4.2 27 16.7 30 18.5 6 3.7 3 1.9
0.22 0.03-1.86 Not estimable 1.07 1.00-1.13 1.18 0.98-1.42 1.15 0.62-2.13 1.06 0.63-1.78 0.91 0.54-1.52 1.59 0.55-4.60 2.27 0.55-9.31
0.128 0.052 0.076 0.667 0.139 0.829 0.711 0.390 0.242
Nulliparous women - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=213 % 3 1.4 0 0.0 210 98.6 159 74.7 40 18.8 9.2 4.0 58 27.2 38 17.8 11 5.2 3 1.4
N=221 % 15 6.8 0 0.0 212 95.9 156 70.6 32 13.8 8.5 4.2 46 20.8 56 25.3 10 4.5 6 2.7
0.20 0.06-0.69 Not estimable 1.03 0.99-1.08 1.05 0.93-1.18 1.27 0.83-1.94 1.31 0.93-1.83 0.70 0.48-1.01 1.12 0.49-2.60 0.54 0.14-2.14
0.011 0.113 0.411 0.279 0.566 0.121 0.056 0.783 0.380
Nulliparous women, BS 0-3 - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=143 % 2 1.4 0 0.0 140 97.9 106 74.1 30 21.0 9.2 3.9 40 28.0 26 18.2 8 5.6 3 2.1
N=126 % 9 7.1 0 0.0 121 96.0 92 73.0 20 15.9 8.7 4.1 23 18.3 35 27.8 7 5.6 4 3.2
0.20 0.04-0.89 Not estimable 1.02 0.98-1.06 1.02 0.89-1.17 1.32 0.79-2.21 1.53 0.97-2.41 0.65 0.42-1.02 1.01 0.38-2.70 0.66 0.15-2.90
0.018 0.368 0.837 0.283 0.153 0.060 0.061 0.989 0.580
Nulliparous women, BS 4-6 - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N= 70 % 1 1.4 0 0.0 70 100.0 53 75.7 10 14.3 8.7 4.2 18 25.7 12 17.1 3 4.3 0 0.0
N= 95 % 6 6.3 0 0.0 91 95.8 64 67.4 12 12.6 8.3 4.2 23 24.2 21 22.1 3 3.2 2 2.1
0.23 0.03-1.84 Not estimable 1.04 1.00-1.09 1.12 0.93-1.36 1.13 0.52-2.47 1.06 0.26-1.81 0.78 0.41-1.47 1.36 0.28-6.52 0.27 0.01-5.55
0.124 0.082 0.243 0.757 0.601 0.825 0.431 0.702 0.222
Multiparous women - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=152 % 1 0.7 0 0.0 141 92.8 84 55.3 19 12.5 5.6 3.1 7 4.6 19 12.5 6 4.0 5 3.3
N=155 % 2 1.3 0 0.0 135 87.1 73 47.1 20 12.9 5.2 3.0 17 11.0 21 13.6 10 6.5 3 1.9
0.49 0.05- 5.38 Not estimable 1.07 0.99- 1.15 1.17 0.94- 1.45 0.94 0.52- 1.69 0.42 0.18- 0.98 0.91 0.51- 1.63 0.60 0.22- 1.62 1.79 0.43- 7.41
0.561 0.087 0.173 0.834 0.825 0.046 0.764 0.313 0.420
Multiparous women, BS 0-3 - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=103 % 1 1.0 0 0.0 96 93.2 57 55.3 13 12.6 5.3 3.1 4 3.9 11 10.7 2 1.9 0 0.0
N= 88 % 2 2.3 0 0.0 79 89.8 45 51.1 13 14.8 5.3 2.6 13 14.8 12 13.6 7 8.0 2 2.3
0.43 0.04- 4.63 Not estimable 1.04 0.95- 1.13 1.08 0.83- 1.41 0.85 0.42- 1.75 0.26 0.09- 0.78 0.78 0.36- 169 0.24 0.05- 1.14 0.17 0.01- 3.52
0.471 0.394 0.562 0.666 0.850 0.008 0.531 0.051 0.124
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Misoprostol Group PGE2 Group Treatment Effect RR 95% CI
P value
Multiparous women, BS 4-6 - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N= 49 % 0 0.0 0 0.0 45 91.8 27 55.1 6 12.2 6.2 3.3 3 6.1 8 16.3 4 8.2 5 10.2
N= 67 % 0 0.0 0 0.0 56 83.6 28 41.8 7 10.5 5.0 3.5 4 6.0 9 13.4 3 4.5 1 1.5
Not estimable Not estimable 1.10 0.96- 1.23 1.32 0.90- 1.93 1.17 0.42- 3.27 1.03 0.24- 4.38 1.22 0.51- 2.92 1.82 0.43- 7.78 6.83 0.82-56.68
0.191 0.156 0.762 0.068 0.973 0.663 0.410 0.364
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect. Statistically significant results (p<0.05) in bold text.
* Mean and standard deviation (interval in hours); Student’s T-Test
HSS = hyperstimulation syndrome
FHR = fetal heart rate
3.4(7)(v) Secondary Analysis – Neonatal Complications
There was no correlation in infant outcomes based on maternal parity or initial cervical
score.
3.4(7)(vi) Secondary Analysis – Maternal Complications
Women with an initial Bishop’s score of 0-3 who were administered misoprostol were
less likely to experience nausea when compared with women administered PGE2
(Misoprostol 11/246 (4.5%) versus PGE2 20/214 (9.4%); RR 0.48 95% CI 0.23-0.98;
p=0.038). Nulliparous women administered misoprostol were less likely to experience
any side effect (Misoprostol 39/213 (18.3%) versus PGE2 63/221 (28.5%); RR 0.63
95% CI 0.45-0.90; p=0.011), or vomiting when compared with PGE2 (Misoprostol
1/213 (1.1%) versus PGE2 9/221 (4.1%); RR 0.12 95% CI 0.02-0.95; p=0.044), but
otherwise there was no correlation between experience of side effects and maternal
parity.
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Table 3.4(7)(vi) Secondary Analysis – Maternal Complications
Misoprostol Group
PGE2 Group Treatment Effect RR 95% CI
P value
All women - Any side effect - Nausea - Vomiting - Diarrhoea - Flushing
N=365 % 76 20.8 20 5.5 4 1.1 5 1.4 6 1.6
N=376 % 99 26.3 30 8.0 10 2.7 9 2.4 4 1.1
0.78 0.60- 1.01 0.68 0.39- 1.19 0.43 0.14- 1.37 0.53 0.18- 1.57 1.43 0.41- 5.05
0.063 0.175 0.154 0.250 0.578
Bishop’s Score 0-3 - Any side effect - Nausea - Vomiting - Diarrhoea - Flushing
N=246 % 55 22.4 11 4.5 2 0.8 4 1.6 5 2.0
N=214 % 59 27.6 20 9.4 5 2.3 7 3.3 3 1.4
0.81 0.59- 1.12 0.48 0.23- 0.98 0.35 0.07- 1.78 0.50 0.15- 1.67 1.45 0.35- 6.00
0.197 0.038 0.183 0.294 0.606
Bishop’s Score 4-6 - Any side effect - Nausea - Vomiting - Diarrhoea - Flushing
N=119 % 21 17.7 9 7.6 2 1.7 1 0.8 1 0.8
N=162 % 40 24.7 10 6.2 5 3.1 2 1.2 1 0.6
0.71 0.45- 1.15 1.22 0.51- 2.92 0.54 0.11- 2.76 0.68 0.06- 7.42 1.36 0.09-21.55
0.157 0.647 0.455 0.751 0.826
Nulliparous women - Any side effect - Nausea - Vomiting - Diarrhoea - Flushing
N=213 % 39 18.3 11 5.2 1 0.5 4 1.9 3 1.4
N=221 % 63 28.5 19 8.6 9 4.1 6 2.7 2 0.9
0.63 0.45- 0.90 0.60 0.29- 1.23 0.12 0.02- 0.94 0.64 0.18- 2.24 1.45 0.24- 8.58
0.011 0.162 0.044 0.487 0.686
Multiparous women - Any side effect - Nausea - Vomiting - Diarrhoea - Flushing
N=152 % 37 24.3 9 5.9 3 2.0 1 0.7 3 2.0
N=155 % 36 23.2 11 7.1 1 0.7 3 1.9 2 1.3
1.03 0.69- 1.54 0.83 0.35- 1.95 3.21 0.34-30.58 0.31 0.03- 2.97 1.41 0.24- 8.34
0.880 0.669 0.311 0.311 0.704
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect. Statistically significant results (p<0.05) in bold text.
3.5 DISCUSSION
This randomised trial is the second double blind, placebo controlled study comparing
oral misoprostol with vaginal PGE2 gel, and the first involving low dose oral
misoprostol solution for the induction of labour at term. The importance of blinding
participants and caregivers to treatment allocation in randomised trials has been well
described (Chalmers1989; Schulz 1995; Kunz 1998). The blinding of women,
caregivers and outcome assessors employed in this trial reduced the potential for bias
and increases confidence in the validity of these results. The inclusion criteria
represented the spectrum of indications for induction of labour, and with over 70% of
women approached agreeing to participate in the trial, these results have external
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validity and are applicable to the general obstetric population requiring induction of
labour at term.
This trial has the largest sample size to date of the randomised trials described
comparing oral misoprostol and vaginal PGE2 gel, and was adequately powered to
detect clinically important differences in caesarean birth and vaginal birth not achieved
within 24 hours. This trial, however, was powered to detect relatively large differences
in the less common outcome of uterine hyperstimulation with associated fetal heart rate
changes (72% difference from 2% in the vaginal PGE2 group to 6% in the oral
misoprostol group). For the rare, but serious maternal and neonatal complications, such
as death and morbidity, including maternal uterine rupture and neonatal acidosis, the
study was under-powered to detect all but large differences. Given the low frequency of
occurrence of these serious adverse outcomes, it would be necessary to recruit into a
trial tens of thousands of women and their infants, an extremely unlikely scenario to be
successfully achieved in a single study. Nevertheless, the results from this study provide
reliable evidence from a randomised controlled trial on the use of oral misoprostol for
the induction of labour at term, can be included into a meta-analysis with other
randomised controlled trials in future systematic reviews of the literature, and contribute
to the available information about the safety of oral misoprostol for rare but serious
maternal and infant adverse events.
For the primary study outcomes of vaginal birth not achieved in 24 hours, caesarean
birth, and uterine hyperstimulation syndrome with associated fetal heart rate changes,
there were no statistically significant differences between oral misoprostol and vaginal
PGE2 gel.
In considering the secondary outcomes relating to evidence of effect, oral misoprostol
was less effective than vaginal PGE2 gel, as indicated by more women with a Bishop’s
score of less than seven 24 hours after the induction commenced, more women
requiring further doses of known prostaglandin E2 gel, more women requiring an
oxytocin infusion during labour (including either induction or augmentation of labour),
and a longer induction to birth interval. However, there were no differences in the mean
length of labour for these women, suggesting that progress of labour, once established,
occurred at a similar rate, regardless of the induction agent utilised.
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The findings from this trial indicate no difference in maternal side effects or serious
maternal complications in women administered oral misoprostol when compared with
women administered vaginal PGE2 gel. Similarly there was a low incidence of neonatal
Apgar score of less than five at seven minutes of age and cord pH of less than 7.18,
outcomes that have traditionally been used as surrogate markers of the more severe
outcome of neonatal acidemia. Any modification or increase in the dose of oral
misoprostol, while improving clinical efficacy, must be balanced against a potential
increase in these unwanted adverse outcomes.
The secondary analyses were conducted to explore the effects of maternal parity
(nulliparous versus multiparous) and initial Bishop’s score (Bishop’s score 0-3 versus
Bishop’s score 4-6) on the primary and secondary study outcomes. There was no
apparent effect on the primary study outcomes for women with an initial Bishop’s score
of 0-3, nulliparous women, and nulliparous women with an initial Bishop’s score of 0-3.
There were more women in the misoprostol group with an initial Bishop’s score of 0-3,
and even though corrections were made in the subsequent analyses, there may be
potential for the introduction of bias into these results, tending towards more favourable
reporting of outcomes in the vaginal PGE2 gel group.
The risk of caesarean section was not associated with maternal parity (nulliparous
versus multiparous) or Bishop’s score (Bishop’s score 0-3 versus Bishop’s score 4-6).
However, for all women with an extremely unfavourable cervix (Bishop’s score 0-3),
induction of labour was associated with an increased risk of caesarean birth (28%),
when compared with women with a more favourable cervix (Bishop’s score 4-6) (20%),
highlighting the considerable risks associated with induction of labour in the presence
of an unfavourable cervix. The implications of caesarean birth relate not only to the
increased risk of complications in the index pregnancy when compared with vaginal
birth, but also to future childbearing and subsequent mode of birth in the presence of a
uterine scar. Caution should therefore be exercised when contemplating induction of
labour in women with an extremely unfavourable cervix, to ensure that there is no
opportunity to delay the procedure to allow for spontaneous improvement in the
cervical score.
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Nulliparous women administered oral misoprostol, and particularly those nulliparous
women with a highly unfavourable cervix (Bishop’s score of 0-3), were more likely to
still have an unfavourable cervix (Bishop’s score of less than seven) 24 hours after the
induction commenced, and to receive further doses of vaginal PGE2 gel. Nulliparous
women, regardless of initial Bishop’s score had a longer induction to birth interval,
although there were no differences in the mean length of labour between women in the
oral misoprostol group and those in the vaginal PGE2 gel group, again suggesting that
the longer induction to birth interval reflects an increase in the duration of time prior to
establishing in labour, rather than a prolongation of labour itself.
Fewer nulliparous women administered oral misoprostol experienced hyperstimulation
syndrome without associated fetal heart rate changes when compared with those women
administered vaginal PGE2 gel, an effect again most pronounced for nulliparous women
with an initial Bishop’s score of 0-3, and suggestive of the possible need for an increase
in the dose administered to this group of women.
The findings of reduced efficacy associated with misoprostol raise the possibility that
the dosing regimen of 20mcg at two hourly intervals used in this trial may have been
inadequate. Women administered misoprostol had a significant reduction of 79% in the
occurrence of uterine hyperstimulation without associated fetal heart rate changes, and
while this may represent a true reduction in the incidence of side effects with
misoprostol, in the context of evidence of reduced efficacy it is more consistent with an
inappropriately low dose administered. In this regard, an incremental increase in dose to
40mcg after four hours in the absence of uterine activity as described by Hofmeyr
(2001) and later Dallenbach (2003) may be more appropriate.
For multiparous women, the dose of 20mcg at 2 hourly intervals is as effective as
vaginal PGE2 gel in that similar numbers of women in each group did not achieve
vaginal birth in 24 hours, showed no evidence of cervical change, or required additional
doses of vaginal PGE2 gel. Multiparous women administered misoprostol were less
likely to require an instrumental vaginal birth, and while there was an increased need
for oxytocin infusion, there was a reduction in the need for further doses of vaginal
PGE2 gel after 12 hours. Importantly, there was no documented increase in potential
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adverse effects such as uterine hyperstimulation with associated fetal heart rate changes,
or caesarean section.
These findings are in keeping with the clinical observation of increased ease in inducing
labour in multiparous women compared with nulliparous women, and accepted
differences in the dose of PGE2 vaginal gel used on the basis of a woman’s parity. The
vaginal gel dosing regimen adopted in this trial is consistent with current South
Australian Perinatal Guidelines recommending a dose of 1mg vaginal PGE2 be used in
multiparous women and 2mg vaginal PGE2 in nulliparous women (Government SA
2005). In this current trial, an identical dose of oral misoprostol of 20mcg at two hourly
intervals was used for both multiparous and nulliparous women.
The outcome vaginal birth not achieved in 24 hours as defined in the Cochrane generic
protocol (Hofmeyr 2005a) comprises both women who birth vaginally beyond 24 hours
and all women who birth by caesarean section. These two components reflect different
processes whereby misoprostol may generate adverse health outcomes. If vaginal birth
is achieved beyond 24 hours, this may reflect an inappropriately low dose of
misoprostol as suggested in this study by other outcomes related to clinical efficacy.
The alternative process contributing to adverse health outcomes relates to uterine
hyperstimulation with fetal heart rate changes and subsequent birth by caesarean section
for non-reassuring fetal heart rate trace. The results of this study indicate a relative
reduction in caesarean birth with the use of misoprostol of the order of 18%. For
completeness and to ensure clarity of information, future trials should report both
components of this outcome.
3.6 CONCLUSION
Oral misoprostol was not associated with differences in the number of women who
achieve vaginal birth in 24 hours, uterine hyperstimulation with fetal heart rate changes,
or caesarean section, compared with vaginal PGE2 gel. Its use was associated with more
women having an unfavourable cervix 24 hours after commencing the induction, an
increased need for further doses of vaginal PGE2 gel and oxytocin infusion, but a
significant reduction in uterine hyperstimulation without fetal heart rate changes.
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Importantly, these differences in the process of induction of labour were not associated
with an increase in the risk adverse health outcomes for the woman or her infant.
An initial Bishop’s score of 0-3 and nulliparity were both independently associated with
greater difficulty in inducing labour, particularly when using misoprostol. However,
these differences in the process of initiating labour were not associated with an increase
in the risk of adverse health outcomes for the woman or her infant. For nulliparous
women, and particularly those with an extremely unfavourable cervix (as indicated by a
Bishop’s score of 0-3), a dose of 20mcg of misoprostol at two hourly intervals is less
effective when compared with the standard vaginal PGE2 gel. Further information is
required about the lowest dose of misoprostol that will attain clinical effect for this
group of women who require induction of labour. Any further increase in the oral dose
administered, while generating beneficial effects of improved clinical efficacy, must be
balanced against the potential increase in unwanted side effects for the woman, and
uterine hyperstimulation, both with and without fetal heart rate changes. While there is
no apparent difference in the length of labour for this group of women, additional
information is required about women’s satisfaction, particularly those women who
remain undelivered after 24 hours.
The dose of 20mcg of misoprostol at two hourly intervals utilised in this trial is as
effective as the standard vaginal PGE2 gel for multiparous women requiring induction
of labour, and should be available for use within institutions.
Misoprostol is not associated with fewer women achieving vaginal birth within 24
hours, or an increased risk of caesarean section, uterine hyperstimulation with fetal
heart rate changes, or adverse health outcomes for women or their infants. In view of
the relative safety of this low dose of misoprostol in the induction of labour, women’s
satisfaction, and particularly for those women not achieving vaginal birth within 24
hours, needs to be incorporated into any future clinical recommendation regarding the
widespread or routine use of misoprostol.
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4. WOMEN’S PREFERENCES FOR CARE
4.1 INTRODUCTION While induction of labour is common, there is limited information available relating to
women’s experiences and preferences for care. There is a current shift in health care
policy and practice to incorporate women’s preferences for health related outcomes,
with the aim of providing more individualised care. The assessment of women’s
preferences is therefore of great importance in the evaluation of any new healthcare
intervention. This study was designed to assess both midwives’ and women’s
satisfaction with and preferences for care in relation to methods of induction of labour.
4.2 STUDY AIMS AND HYPOTHESES
The use of oral misoprostol is
• Women’s preferred method of induction of labour when compared with vaginal
prostaglandin E2 gel; and
• Caregiver’s preferred method of induction of labour when compared with
vaginal prostaglandin E2 gel.
4.3 METHODS
This randomised, double blind, placebo controlled trial comparing oral misoprostol with
vaginal prostaglandin E2 gel for the induction of labour was performed at the Women’s
and Children’s Hospital, the Lyell McEwin Health Service, and Hervey Bay Hospital
between April 2001 and December 2004. Women were recruited from the antenatal
clinic, antenatal wards and delivery suite of participating institutions, with research and
ethics committee approval from each collaborating centre as described previously.
Following birth, and prior to discharge from hospital, women were asked to complete a
short questionnaire detailing their experiences of induction of labour. Women were
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asked to indicate their level of satisfaction with the induction process, their labour, and
their birth (categorised into unsatisfied = not at all or mildly satisfied, and satisfied =
moderately or extremely satisfied). A list of likes and dislikes relating to the induction
process were provided, in addition to a text field in which women could make further
comments. Women were asked to mark all applicable statements relating to their likes
and dislikes. Additionally, women were asked to nominate the group to which they
thought they belonged (oral misoprostol, vaginal prostaglandin E2 gel, or uncertain), as
well as their preferences for method of induction in a future pregnancy should it be
required. An identical questionnaire was posted to each woman approximately six
weeks after birth. Women who did not return the questionnaire by mail were
telephoned, and the questionnaire completed over the phone.
A questionnaire was completed by the midwife primarily responsible for the care of the
woman during the induction process, detailing satisfaction with the method (categorised
into unsatisfied = not at all or mildly satisfied, and satisfied = moderately or extremely
satisfied), preferences for induction methods to be used in the future, as well as asking
an indication of the group the woman was thought to belong to (oral misoprostol,
vaginal prostaglandin E2 gel, or uncertain).
Results were analysed on an intention-to-treat basis and blind to the allocated treatment
using the SAS Version 9.1 statistical software programme (SAS Institute Incorporated
2003). Baseline data were examined by treatment group to ensure comparability for
prognostic factors as described previously, with adjustment for imbalance in the initial
Bishop’s score, using log binomial regression techniques. The outcomes were compared
using χ2 tests and Fisher’s Exact Test, with calculation of relative risks (RR) with 95%
Confidence Intervals (CI). A planned secondary analysis related to exploration of any
differences in satisfaction for those women who remained undelivered 24 hours after
the induction process commenced. A p value of less than 0.05 was considered
statistically significant.
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4.4 RESULTS
4.4(1) Baseline characteristics
A total of 1319 eligible women were approached for trial participation by a clinical
researcher at the time of booking the induction of labour, of whom 939 provided written
consent to participate (71.2%)(Figure 3.4(1)). Of those consenting women, 199 (21.2%)
entered labour spontaneously prior to the date of booked induction of labour, and
741(78.8%) were admitted for induction of labour and randomised to the trial. Three
hundred and 65 women were randomised to the oral misoprostol group, and 376 to the
vaginal PGE2 group. Data on women’s preferences for care at the time of hospital
discharge were available for 739 (99.7%) women. Six-week questionnaires were
available from 735 (99.2%) women. Baseline characteristics were comparable between
the treatment groups, with the exception of initial Bishop’s score as described
previously (Table 3.4(1)), and adjustment for this imbalance in the planned analyses
was required.
4.4(2) Women’s Satisfaction and Preferences for Care at Discharge
All 739 (100%) women for whom satisfaction questionnaires were available, were
satisfied with the care that they received (Table 4.4(2)). The number of women who
were not satisfied (defined as either not at all satisfied or only mildly satisfied) with
their induction were similar between the oral misoprostol and vaginal PGE2 gel groups
(Misoprostol 68/365 (18.6%) versus PGE2 72/374 (19.3%); RR 0.97 95% CI 0.72-1.31;
p=0.840), as were those unsatisfied with their labour (Misoprostol 84/365 (23.0%)
versus PGE2 73/374 (19.5%); RR 1.17 95% CI 0.89-1.55; p=0.266) and birth
(Misoprostol 51/365 (14.0%) versus PGE2 53/374; RR 1.01 95% CI 0.71-1.45;
p=0.949). Overall, 74.3% of women, given similar circumstances, would participate in
the study again, and 83.2% of women would recommend a friend in similar
circumstances participate in the study, figures that were not significantly different
between the two treatment groups. Women in the misoprostol group were more likely to
correctly identify the group to which they had been allocated (Misoprostol 132/365
(36.2%) versus PGE2 91/374 (24.3%); RR 1.49 95% CI 1.19-1.86; p=0.001). Of the
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women participating in the trial, 57.9% indicated a preference for an oral induction
agent, should any future pregnancy require induction of labour, with no differences in
preferences between the two treatment groups. Satisfaction with care did not differ
between women who had given birth within 24 hours of the induction starting, and
those women who remained undelivered after 24 hours.
Table 4.4(2) Women’s Satisfaction and Preferences for Care at
Discharge
Misoprostol Group
PGE2 Group Treatment Effect RR 95% CI
P value
All women - Woman not satisfied with care - Not satisfied with IOL - Not satisfied with labour - Not satisfied with birth - Participate in study again - Recommend others participate in study - Correctly identify group - Preference for oral IOL agent
N=365 % 0 0.0 68 18.6 84 23.0 51 14.0 274 75.1 304 83.3 132 36.2 219 60.0
N=374 % 0 0.0 72 19.3 73 19.5 53 14.2 275 73.1 311 82.3 91 24.3 209 55.9
Not estimable 0.97 0.72-1.31 1.17 0.89-1.55 1.01 0.71-1.45 1.03 0.94-1.12 1.01 0.94-1.07 1.49 1.19-1.86 1.07 0.95-1.21
0.840 0.266 0.949 0.539 0.842 0.001 0.434
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect. Statistically significant results (p<0.05) in bold text.
IOL = induction of labour
4.4(3) Women’s Likes and Dislikes During Induction of Labour at
Discharge
Overall, women’s responses to their participation in the trial were positive, with 29.4%
indicating that they “liked being involved in the study”, and 32.2% indicating that they
“liked everything” during their induction and labour (Table 4.4(3)). Few women (2.3%)
indicated that they “disliked being involved in the study”, or that they “didn’t like
anything” during their induction and labour (9.3%), responses that did not differ for
women in the oral misoprostol group when compared with those in the vaginal PGE2
group (Table 4.4(3)). Women liked the “reassurance that (their) baby was well”
(58.2%), while 18.3% of women indicated that they didn’t like having their baby
monitored. Again, these responses were not different between women in the oral
misoprostol group and those in the vaginal PGE2 group.
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While 39.0% of women indicated that they had no side effects from the medication, and
9.5% few medication side effects, 19.8% of women disliked abdominal cramps, 13.1%
disliked nausea or vomiting, 5.1% disliked hot flushes, 3.8% disliked headaches, and
1.6% disliked diarrhoea. There were no differences in these responses between women
in the oral misoprostol group and those in the vaginal PGE2 group.
The trial protocol required administration of oral medication and fetal heart rate
monitoring at two hourly intervals, and 3.1% of women indicated that they did not like
the interruptions to sleep that this caused, a response that did not differ between those
women in the oral misoprostol group and those in the vaginal PGE2 group.
Likes and dislikes during induction and labour did not differ between women who had
given birth within 24 hours of the induction starting, and those women who remained
undelivered after 24 hours.
Table 4.4(3) Women’s Likes and Dislikes During Induction of Labour
at Discharge
Misoprostol Group
PGE2 Group Treatment Effect RR 95% CI
P value
All women I Liked… - Didn’t like anything - No side effects from medication - Few side effects from medication - Reassurance baby was well - Being involved in this study
N=365 % 35 9.6 142 38.9 34 9.3 214 58.6 104 28.5
N=374 % 34 9.0 146 38.8 36 9.6 216 57.5 113 30.1
1.08 0.69-1.71 1.00 0.83-1.20 0.96 0.61-1.51 1.02 0.90-1.15 0.94 0.75-1.17
0.724 0.985 0.866 0.770 0.564
I Disliked… - Like everything - Nausea or vomiting - Diarrhoea - Abdominal cramps - Headaches - Hot flushes - Too many internal examinations - Having the baby monitored - Being involved in this study - Lack of sleep
123 33.7 46 12.6 5 1.4 63 17.3 11 3.0 13 3.6 98 26.9 65 17.8 9 2.5 9 2.5
115 30.6 51 13.6 7 1.9 83 22.1 17 4.5 25 6.7 103 27.4 70 18.6 8 2.1 14 3.7
1.11 0.90-1.37 0.94 0.65-1.38 0.75 0.24-2.34 0.78 0.58-1.04 0.66 0.31-1.39 0.53 0.27-1.02 0.95 0.75-1.20 0.98 0.72-1.33 1.21 0.47-3.12 0.64 0.28-1.46
0.319 0.784 0.616 0.092 0.272 0.058 0.642 0.893 0.692 0.288
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect. Statistically significant results (p<0.05) in bold text.
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4.4(4) Midwives’ Satisfaction and Preferences for Care
The primary midwife responsible for care during the induction process completed a
staff satisfaction questionnaire, and there were no differences in the number of
midwives not satisfied (defined as not at all satisfied or only mildly satisfied) with the
induction process (Misoprostol 102/365 (27.9%) versus PGE2 107/374 (28.6%); RR
0.94 95% CI 0.75-1.18; p=0.612)(Table 4.4(4)). Midwives caring for women in the
misoprostol group were more likely to correctly identify the group to which the woman
was allocated (Misoprostol 108/365 (29.6%) versus PGE2 84/374 (22.5%); RR 1.32
95% CI 1.03-1.68; p=0.049). Overall, 65.1% of midwives indicated a preference for an
oral induction of labour agent.
Table 4.4(4) Midwives’ Satisfaction and Preferences for Care
Misoprostol Group
PGE2 Group Treatment Effect RR 95% CI
P value
All women - Carer not satisfied - Carer correctly identify group - Carer preference for oral IOL agent
N=365 % 102 27.8 108 29.6 240 65.8
N=374 % 107 28.6 84 22.5 241 64.4
0.94 0.75-1.18 1.32 1.03-1.68 1.02 0.92-1.13
0.612 0.049 0.619
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect. Statistically significant results (p<0.05) in bold text.
IOL = induction of labour
4.4(5) Women’s Satisfaction and Preferences for Care at 6 weeks
Postpartum
Of the 735 women for whom satisfaction questionnaires were available, 99.7% were
satisfied with the care that they received (Table 4.4(5)). The number of women who
were not satisfied (defined as either not at all satisfied or only mildly satisfied) with
their induction were similar between the oral misoprostol and vaginal PGE2 gel groups
(Misoprostol 77/362 (21.3%) versus PGE2 79/373 (21.2%); RR 1.00 95% CI 0.76-1.33;
p=0.975), as were those unsatisfied with their labour (Misoprostol 83/362 (22.9%)
versus PGE2 80/373 (21.4%); RR 1.07 95% CI 0.82-1.40; p=0.600) and birth
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(Misoprostol 48/362 (13.3%) versus PGE2 50/373 (13.4%); RR 0.99 95% CI 0.68-1.43;
p=0.990).
Overall, 70.6% of women, given similar circumstances, would participate in the study
again, and 80.5% of women would recommend a friend in similar circumstances
participate in the study, figures that were not significantly different between the two
treatment groups. Women in the misoprostol group were more likely to correctly
identify the group to which they had been allocated (Misoprostol 135/362 (37.3%)
versus PGE2 89/373 (23.9%); RR 1.49 95% CI 1.19-1.86; p=0.001). Of the women
participating in the trial, 58.5% indicated a preference for an oral induction agent,
should any future pregnancy require induction of labour, with no differences in
preferences between the two treatment groups.
At six weeks post-partum, satisfaction with care did not differ between women who had
given birth within 24 hours of the induction starting, and those women who remained
undelivered after 24 hours.
Table 4.4(5) Women’s Satisfaction and Preferences for Care at 6 weeks
Postpartum
Misoprostol Group
PGE2 Group Treatment Effect RR 95% CI
P value
All women - Woman not satisfied with care - Not satisfied with IOL - Not satisfied with labour - Not satisfied with birth - Participate in study again - Recommend others participate in study - Correctly identify group - Preference for oral IOL agent
N=362 % 0 0.0 77 21.3 83 22.9 48 13.2 263 72.7 296 81.8 135 37.3 215 59.4
N=373 % 2 0.5 79 21.2 80 21.4 50 13.4 256 68.6 296 79.4 89 23.4 215 57.6
0.21 0.01-4.28 1.00 0.76-1.33 1.07 0.82-1.40 0.99 0.68-1.43 1.06 0.96-1.16 1.03 0.96-1.11 1.49 1.19-1.86 1.03 0.91-1.16
0.466 0.975 0.600 0.990 0.238 0.421 0.001 0.348
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect. Statistically significant results (p<0.05) in bold text.
IOL = induction of labour
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4.4(6) Women’s Likes and Dislikes During Induction of Labour at 6
weeks Postpartum
Overall, women’s responses to their participation in the trial were positive, with 31.7%
indicating that they “liked being involved in the study”, and 31.2% indicating that they
“liked everything” during their induction and labour (Table 4.4(6)). More women in the
misoprostol group indicated that they “liked everything” when compared with women
in the vaginal PGE2 group (Misoprostol 126/362 (34.8%) versus PGE2 103/373
(27.6%); RR 1.26 95% CI 1.02-1.57; p=0.036). Few women (5.2%) indicated that they
“disliked being involved in the study”, or that they “didn’t like anything” during their
induction and labour (9.4%), responses that did not differ for women in the oral
misoprostol group when compared with those in the vaginal PGE2 group (Table 4.4(6)).
Women liked the “reassurance that (their) baby was well” (62.4%), while 18.5% of
women indicated that they didn’t like having their baby monitored. Again, these
responses were not different between women in the oral misoprostol group and those in
the vaginal PGE2 group.
While 43.5% of women indicated that they had no side effects from the medication, and
8.3% few medication side effects, 16.1% of women disliked abdominal cramps, 12.7%
disliked nausea or vomiting, 3.4% disliked hot flushes, and 1.8% disliked diarrhoea.
There were no differences in these responses between women in the oral misoprostol
group and those in the vaginal PGE2 group. Women in the misoprostol group were less
likely to experience headaches when compared with women in the vaginal PGE2 group
(Misoprostol 9/362 (2.5%) versus PGE2 23/373 (6.2%); RR 0.43 95% CI 0.19-0.86;
p=0.015).
The trial protocol required administration of oral medication and fetal heart rate
monitoring at two hourly intervals, and 2.2% of women indicated that they did not like
the interruptions to sleep that this caused, a response that did not differ between those
women in the oral misoprostol group and those in the vaginal PGE2 group.
Of women who remained undelivered 24 hours after commencing the induction, more
women in the misoprostol group indicated that they “liked everything” during their
induction and labour when compared with women in the vaginal PGE2 group
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(Misoprostol 26/130 (20.0%) versus PGE2 9/98 (9.2%); RR 2.18 95% CI 1.07-4.44;
p=0.025). Likes and dislikes during induction and labour otherwise did not differ
between women who had given birth within 24 hours of the induction starting, and
those women who remained undelivered after 24 hours.
Table 4.4(6) Women’s Likes and Dislikes During Induction of Labour
at 6 weeks Postpartum
Misoprostol Group
PGE2 Group Treatment Effect RR 95% CI
P value
All women I Liked… - Didn’t like anything - No side effects from medication - Few side effects from medication - Reassurance baby was well - Being involved in this study
N=362 % 34 9.4 162 44.8 24 6.6 230 65.5 106 29.3
N=373 % 35 9.4 158 42.4 37 9.9 229 61.4 127 34.0
1.00 0.64-1.57 1.06 0.90-1.25 0.67 0.41-1.09 1.03 0.93-1.16 0.86 0.69-1.06
0.998 0.516 0.106 0.554 0.165
I Disliked… - Like everything - Nausea or vomiting - Diarrhoea - Abdominal cramps - Headaches - Hot flushes - Too many internal examinations - Having the baby monitored - Being involved in this study - Lack of sleep
126 34.8 40 11.0 5 1.4 51 14.1 9 2.5 15 4.1 93 25.7 72 19.9 17 4.7 6 1.6
103 27.6 53 14.2 8 2.1 67 18.0 23 6.2 10 2.7 120 32.2 64 17.2 21 5.6 10 2.7
1.26 1.02-1.57 0.78 0.53-1.14 0.64 0.21-1.95 0.78 0.56-1.10 0.43 0.19-0.86 1.54 0.70-3.39 0.80 0.64-1.00 1.16 0.64-1.57 0.83 0.45-1.55 0.62 0.23-1.68
0.036 0.198 0.432 0.153 0.015 0.274 0.053 0.342 0.567 0.342
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect. Statistically significant results (p<0.05) in bold text.
4.5 DISCUSSION
There is a current shift in health care policy and practice to incorporate women’s
preferences for health related outcomes, with the aim of providing more individualised
and personalised care. As highlighted by Hofmeyr and colleagues (2001), and in the
Cochrane review on oral misoprostol for the induction of labour (Alfirevic 2005), there
is a need for information about women’s satisfaction and preferences for care during
induction of labour. This is the first randomised controlled trial comparing oral
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misoprostol and vaginal PGE2 gel for induction of labour at term to specifically obtain
women’s views on the care they received, with follow-up to six weeks postpartum
available for over 99% of women. However, as all women received both oral and
vaginal preparations, it was not possible to specifically assess women’s experiences
related to the individual methods of induction of labour. The use of a vaginal placebo
necessitated all women undergoing vaginal examination, a factor that may have
influenced their overall preferences and perception of trial participation.
Overall, women were highly satisfied with the care received, and with their induction,
labour and birth, findings that did not differ between women in the oral misoprostol
group and women in the vaginal PGE2 group. Women’s experiences of participation in
the study were similarly high, with the majority of women willing to participate again if
they found themselves in similar circumstances, and would recommend participation to
a friend. These findings suggest that for the majority of women, induction of labour and
birth is a positive experience.
Almost 60% of women indicated a preference for the availability of an oral induction of
labour agent, indicating a high degree of acceptability among women participating in
the trial. This, in conjunction with 27% of women indicating a dislike for the number of
internal examinations during induction and labour, highlights the invasive nature of
vaginal examinations for a woman, and the negative impact it can have on a woman’s
birth experience.
Current guidelines from both the Royal Australian and New Zealand College of
Obstetricians and Gynaecologists (RANZCOG 2001), and the Royal College of
Obstetricians and Gynaecologists (RCOG 2001) recommend electronic fetal heart rate
monitoring in settings where labour is induced. Almost 60% of women in this trial
indicated that they liked the reassurance fetal heart rate monitoring provided, while less
than 20% of women involved indicated that they did not like fetal heart rate monitoring.
This positive view expressed by women is supportive of the current trial protocol,
which required intensive fetal heart rate monitoring for 40-minute periods at two hourly
intervals in relation to the administration of oral medication.
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Findings at 6 weeks postpartum were similar to those obtained prior to discharge from
hospital, with women expressing a high degree of satisfaction with their induction
(81.1% at discharge versus 78.8% at six weeks postpartum), labour (78.8% at discharge
versus 77.8% at six weeks postpartum), and birth (85.9% at discharge versus 86.7% at
six weeks postpartum). Women’s willingness to participate in the study again was
similar at both time points (74.3% at discharge versus 70.6% at six weeks postpartum),
as was their recommendation to a friend (83.2% at discharge versus 80.5% at six weeks
postpartum), and their preference for an oral medication (57.9% at discharge versus
58.5% at six weeks postpartum). The likes and dislikes related to induction expressed
by women at six weeks post-partum were similar to those expressed at the time of
discharge from hospital, however, women in the misoprostol group were more likely to
indicate that they “liked everything” in relation to their induction, labour and birth,
when compared with women in the vaginal PGE2 group.
Women who remained undelivered 24 hours or more after the induction process
commenced were not different in the degree of satisfaction expressed with their
induction, labour or birth, when compared with women who birthed in less than 24
hours. Of women who remained undelivered after 24 hours, more women in the
misoprostol group indicated that they “liked everything” associated with their induction,
labour and birth, when compared with women in the vaginal PGE2 group. While women
in the misoprostol group were more likely to remain undelivered after 24 hours, this
does not appear to have affected their labour and birth experience in a negative fashion.
4.6 CONCLUSION
Women participating in this randomised trial have indicated a strong preference for the
availability of an oral agent to induce labour, and have indicated that the electronic fetal
heart rate monitoring required under the trial protocol provided them with reassurance
that their baby was “well”. Women administered misoprostol were more likely to “like
everything” in relation to their induction, labour and birth experience.
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5. TIME OF COMMENCING INDUCTION OF LABOUR – A NESTED RANDOMISED CONTROLLED TRIAL
5.1 INTRODUCTION There is a well-documented diurnal variation in the concentrations of steroid hormones
in blood, plasma and urine in pregnant women, with a nadir in progesterone
(Runnebaum 1972; Junkermann 1982; Walsh 1984), estrone, estriol and estradiol
(Challis 1980; Reck 1988; Bernstein 1989) concentrations documented in the early
hours of the morning. In contrast, oxytocin concentrations demonstrate a reciprocal
relationship, with greater concentrations measured in the evening and night (Lindow
1996), correlating with a documented nocturnal increase in uterine activity (Hirst 1991;
Hirst 1993).
There have been several clinical studies that have retrospectively assessed diurnal
variations in onset of labour in women both at term (Fraser 1989; Cagnacci 1998;
Mancuso 2004), and before term (Cooperstock 1987; Lindow 2000). These studies
consistently demonstrate a peak in the onset of labour in the evening and early hours of
the morning. Traditionally, women booked for induction of labour have been admitted
to hospital in the evening, with the process of cervical ripening taking place overnight,
in the expectation that women will labour and give birth during daylight hours.
Physiologically, evening may not be the most appropriate time to commence the
induction process, but may represent more closely the optimal time to be in active
labour.
Birth during daylight hours may be beneficial in terms of neonatal outcomes, as there
have been several reports documenting an increase in the risk of early neonatal
mortality, particularly related to asphyxial causes for infants who are born during the
night when compared with those infants born during the day (Chalmers 1998; Stewart
1998; Heller 2000; Luo 2001). Using the Swedish Birth Registry, Luo and Karlberg
(2001) have reviewed over two million births between 1973 and 1995 and assessed the
effect of time of birth on infant outcomes, as well as identifying particular periods of
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time considered to be “high risk”. For all births occurring at night (defined as between
9pm and 7am), there was a small increased risk of infant mortality (rate 3.65 day versus
3.81 night; absolute risk 0.16; relative risk 1.04; 95%CI 1.00-1.09), this being greatest
for infants born at less than 37 weeks gestation (rate 39.47 day versus 42.60 night;
absolute risk 3.13; relative risk 1.08; 95%CI 1.01-1.15). In addition, birth between 5pm
and 1am, and around 9am were considered to be “high risk” periods for early neonatal
mortality (Luo 2001).
There have been no randomised trials that have compared the preferences women hold
for timing of admission and induction of labour, in particular morning or evening
admission. This nested randomised trial was conducted to assess the preferences women
have for timing of induction of labour and the impact that timing of the induction
process may have on maternal and infant outcomes.
5.2 STUDY AIMS AND HYPOTHESES
Commencing the process of induction of labour in the morning more closely reflects the
physiological timing of onset of labour, and is associated with fewer women who
remain undelivered 24 hours after the induction process commences.
5.3 METHODS
5.3(1) Trial Design
This nested prospective randomised controlled trial comparing time of admission to
start induction of labour (Morning Admission Group – after 0800 hours versus Evening
Admission Group – after 2000 hours) was conducted at the Women’s and Children’s
Hospital. Women who consented to participation in the main trial (as described
previously) were randomly allocated at the time of booking the induction of labour, to
admission in the morning (0800 hours) or in the evening (2000 hours).
97
Women were recruited from the antenatal clinic, antenatal wards and delivery suite of
participating institutions as described previously. Potentially eligible women presenting
for induction of labour were given the trial information sheet, counselled by a member
of the study team, and encouraged to discuss the study with her family. Written
informed consent was then obtained.
5.3(2) Inclusion and Exclusion Criteria
Inclusion and exclusion criteria were as described previously in relation to the main trial
comparing oral misoprostol with vaginal PGE2 gel (Chapter 3).
5.3(3) Randomisation Schedule
The randomisation schedule was generated by a non-clinical researcher using a
computer generated sequence with variable blocks and stratification for the woman’s
parity (0 and 1-4). Timing of admission (Morning Admission or Evening Admission)
was written on a card, folded, and placed inside sequentially numbered, sealed opaque
envelopes. The envelope was opened after a woman had consented to participation in
the main trial. Treatment packs were prepared by the principal investigator and the
research midwife, and labelled by a non-clinical researcher according to the generated
randomisation schedule accounting for the woman’s parity and time of admission to
delivery suite. The four possible combinations were therefore nulliparous woman and
morning admission, multiparous woman and morning admission, nulliparous woman
and evening admission, and multiparous woman and evening admission. Opening the
treatment pack was the point of randomisation.
5.3(4) Blinding
Women, caregivers and outcome assessors were not blinded to the woman’s time of
admission for induction of labour to start.
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5.3(5) Treatment Allocation
When women who had given written consent to participation in the main trial
comparing oral misoprostol with vaginal PGE2 gel, they were then randomly allocated
to the time of admission for induction of labour to start. Timing of admission (Morning
Admission or Evening Admission) was written on a card, folded, and placed inside
sequentially numbered, sealed opaque envelopes. The envelope was opened after a
woman had consented to participation in the main trial, and the induction of labour
booked with delivery suite in accordance with the instructions written on the card.
At the time of admission to delivery suite for induction of labour, trial entry details were
confirmed. A study number was allocated to the woman, by taking the next identically
appearing, sequentially numbered treatment pack appropriate for her parity and for the
time of admission to delivery suite.
The study number allocated was recorded on the trial entry form. The study treatment
pack was opened, and contained either oral misoprostol and vaginal placebo (tylose
gel), or oral placebo (vitamin B6) and vaginal prostaglandin E2 (Prostin) gel. Each pack
contained a sheet detailing treatment schedules. The treatment packs were kept at 4O
Celsius (although this was not a requirement for misoprostol). Opening the treatment
pack that corresponded to the woman’s parity and time of admission was the point of
randomisation to the timing of induction trial.
5.3(6) Treatment Schedules
The treatment schedules have been described previously in the relation to the main trial
comparing oral misoprostol with vaginal PGE2 gel (Chapter 3).
Following birth, and prior to discharge from hospital, women were asked to complete a
short questionnaire detailing their experiences of induction of labour. Women were
asked to indicate their level of satisfaction with the induction process, their labour, and
their birth (categorised into unsatisfied = not at all or mildly satisfied, and satisfied =
moderately or extremely satisfied). A list of likes and dislikes relating to the induction
process were provided, in addition to a text field in which women could make further
99
comments. Women were asked to mark all applicable statements relating to their likes
and dislikes. An identical questionnaire was posted to each woman approximately six
weeks after birth. Women who did not return the questionnaire by mail were
telephoned, and the questionnaire completed over the phone.
5.3(7) Study Outcome Measures
5.3(7)(i) Primary Study Outcomes
The primary study outcomes were consistent with the Cochrane generic protocol
relating to induction of labour (Hofmeyr 2005a), and have been described in Chapter 3.
The primary outcomes were
• vaginal birth not achieved within 24 hours,
• uterine hyperstimulation with associated fetal heart rate changes,
• caesarean section (all), and
• caesarean section for fetal distress.
5.3(7)(ii) Secondary Study Outcomes
Secondary study outcomes recorded related to evidence of effect, neonatal
complications and maternal complications as described in the Cochrane generic
protocol relating to methods of induction of labour (Hofmeyr 2005a) and have been
described in Chapter 3 (Table 3.3(6)(ii)).
5.3(8) Data Collection
Data forms were completed by the midwife caring for the woman, with information
confirmed and checked by the principal investigator or research midwife prior to the
woman being discharged from hospital. All data were then entered into a database
created in Access ’97 (Microsoft Corporation 1997) by the principal investigator.
5.3(9) Statistical Analysis
Data were analysed on an intention-to-treat basis and blind to the allocated treatment
using the SAS Version 9.1 statistical software programme (SAS Institute Incorporated
100
2003). The primary and secondary outcomes were compared using χ2 tests and Fisher’s
Exact Test, with calculation of relative risks (RR) with 95% Confidence Intervals (CI)
for dichotomous data. Normally distributed continuous data were compared using the
Student’s T-test, and skewed data using non-parametric tests (Wilcoxon Rank Sum).
Pre-specified subgroup analyses were planned to assess any differential effect in
medication received (oral misoprostol versus vaginal PGE2 gel), the effect of maternal
parity (nulliparous versus multiparous) and initial Bishop’s score at commencing
induction (Bishop’s score 0-3 versus Bishop’s score 4-6) on the time of admission for
induction of labour. A p value of less than 0.05 was considered statistically significant.
5.3(10) Sample Size
Using information from the Cochrane review of oral misoprostol for induction of labour
at term (Alfirevic 2005), and figures generated by the Women’s and Children’s Hospital
Clinical Information Service, a sample size of 620 women was calculated to give 80%
power to detect a 50% difference in the number of women undelivered after 24 hours
from 20% in the evening admission group to 30% in the morning admission group
(p<0.05).
5.4 RESULTS
5.4(1) Baseline Characteristics
A total of 1072 eligible women were approached for trial participation by a clinical
researcher at the time of booking the induction of labour, of whom 775 (72.3%)
provided written consent to participate in the timing of induction trial (Figure 5.4(1)).
Of the 775 women who gave consent, 380 (49.0%) women were scheduled for morning
admission and 395 (51.0%) women were scheduled for evening admission. Prior to the
date of induction of labour, 155 (20.0%) women entered labour spontaneously (100
(64.5%) women scheduled for morning admission and 55 (35.5%) women scheduled for
evening admission). Of the 620 (70.0%) women who were admitted for induction and
randomised into the timing of induction trial, 280 (45.2%) were randomised to the
morning admission group and 340 (54.8%) to the evening admission group.
101
In the morning admission group, 138 women received oral misoprostol and 142 women
vaginal PGE2 gel, and in the evening admission group, 167 women received
misoprostol and 173 women vaginal PGE2 gel (Table 5.4(1)). There were 164
nulliparous women (58.6%) in the morning admission group and 201 nulliparous
women (59.1%) in the evening admission group. In the morning admission group, there
were 177 women (63.2%) with an initial Bishop’s score of 0-3, and 203 women
(59.7%) in the evening admission group with an initial Bishop’s score of 0-3.
Figure 5.4(1) Trial Flow Chart
Entered Labour SpontaneouslyPrior to Booked Induction
100 women (12.9%)
Outcome Data Available138 women (100%)
Misoprostol138 women
Outcome Data Available142 women (100%)
Vaginal PGE2142 women
Randomised to Morning Admission Group280 (45.2%) women
Scheduled Morning Admission380 women (49.0%)
Entered Labour SpontaneouslyPrior to Booked Induction
55 women (7.1%)
Outcome Data Available167 women (100%)
Misoprostol167 women
Outcome Data Available173 women (100%)
Vaginal PGE2173 women
Randomised to Evening Admission Group340 (54.8%) women
Scheduled Evening Admission395 women (51.0%)
Eligible Women Consenting775 (72.3%)
Eligible Women Declined297 (27.7%)
Eligible Women Approached1072
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Table 5.4(1) Distribution of Time of Commencing Induction
Morning Admission
N= 280 % Evening Admission N=340 %
Allocated Treatment - Misoprostol - Vaginal PGE2 gel
138 49.3 142 50.7
167 49.1 173 50.9
Bishop’s Score - Bishop’s score 0-3 - Bishop’s score 4-6
177 63.2 103 36.8
203 59.7 137 40.3
Nulliparous women - Bishop’s score 0-3 - Bishop’s score 4-6
164 58.6 102 62.2 62 37.8
201 59.1 119 59.2 82 40.8
Multiparous women - Bishop’s score 0-3 - Bishop’s score 4-6
116 41.4 75 64.7 41 35.3
139 40.9 84 60.4 55 39.6
Figures are numbers and percentages
5.4(2) Time of Commencing Induction and Primary Outcomes
The likelihood of not achieving vaginal birth within 24 hours of starting induction of
labour was not different for women in the morning admission group, when compared
with women in the evening admission group (Morning admission 121/280 (43.2%)
versus Evening admission 151/340 (44.4%); RR 0.97 95% CI 0.81-1.16; p=0.432)
(Table 5.4(2)). The occurrence of uterine hyperstimulation syndrome with associated
fetal heart rate changes (Morning admission 5/280 (1.8%) versus Evening admission
0/340 (0.0%); RR 7.31 95% CI 0.88-60.58; p=0.998), all caesarean sections (Morning
admission 62/280 (22.1%) versus Evening admission 89/340 (26.2%); RR 0.83 95% CI
0.63-1.10; p=0.194) and caesarean section for fetal distress (Morning admission 27/280
(9.6%) versus Evening admission 33/340 (9.7%); RR 0.98 95% CI 0.60-1.59; p=0.934)
did not differ for women in the morning admission group compared with women in the
evening admission group.
There were no differences identified between morning and evening admission and the
induction agent used (misoprostol versus vaginal PGE2 gel), maternal parity
(nulliparous versus multiparous), or initial Bishop’s score (Bishop’s score 0-3 versus
Bishop’s score 4-6) for primary study outcomes.
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Table 5.4(2) Time of Commencing Induction - Primary Outcomes
Morning Admission Evening Admission Treatment Effect RR 95% CI
P value
All women - Vaginal Birth not achieved in 24 hours - Uterine HSS with FHR changes - Caesarean section - all - Caesarean section - fetal distress
N=280 % 121 43.2 5 1.8 62 22.1 27 9.6
N=340 % 151 44.4 0 0.0 89 26.2 33 9.7
0.97 0.81-1.16 7.31 0.88-60.58 0.83 0.63-1.10 0.98 0.60-1.59
0.432 0.997 0.194 0.934
Misoprostol - Vaginal Birth not achieved in 24 hours - Caesarean section - all - Caesarean section – fetal distress
N=138 % 65 47.1 28 20.3 14 10.1
N=167 % 81 48.5
42 25.2 16 9.6
0.97 0.77-1.23 0.78 0.52-1.19 1.04 0.53-2.05
0.581 0.255 0.913
Vaginal PGE2- Vaginal Birth not achieved in 24 hours - Caesarean section - all - Caesarean section – fetal distress
N=142 % 56 39.4 34 23.9 13 9.2
N=173 % 70 40.5 47 27.2 17 9.8
0.97 0.74-1.28 0.87 0.60-1.27 0.92 0.47-1.83
0.587 0.482 0.821
Bishop’s score 0-3 - Vaginal Birth not achieved in 24 hours - Caesarean section – all - Caesarean section – fetal distress
N=177 % 84 47.5 42 23.7 19 10.7
N=203 % 107 52.7 63 31.0 23 11.3
0.90 0.74-1.10 0.76 0.55-1.07 0.95 0.53-1.68
0.633 0.112 0.854
Bishop’s score 4-6 - Vaginal Birth not achieved in 24 hours - Caesarean section – all - Caesarean section – fetal distress
N=103 % 37 35.9 20 19.4 8 7.8
N=137 % 44 32.1 26 19.0 10 7.3
1.12 0.78-1.59 1.02 0.61-1.73 1.06 0.44-2.60
0.465 0.932 0.892
Nulliparous women - Vaginal Birth not achieved in 24 hours - Caesarean section - all - Caesarean section – fetal distress
N=164 % 94 57.3 49 29.9 22 13.4
N=201 % 115 57.2 71 35.3 23 11.4
1.00 0.84-1.20 0.83 0.61-1.11 1.16 0.67-2.00
0.284 0.208 0.601
Nulliparous women, BS 0-3 - Vaginal Birth not achieved in 24 hours - Caesarean section - all - Caesarean section – fetal distress
N=102 % 66 64.7 32 31.4 15 14.7
N=119 % 82 68.9 50 42.0 16 13.5
0.94 0.78- 1.13 0.75 0.52-1.07 1.09 0.57-2.10
0.297 0.103 0.788
Nulliparous women, BS 4-6 - Vaginal Birth not achieved in 24 hours - Caesarean section - all - Caesarean section – fetal distress
N= 62 % 28 45.2 17 27.4 7 11.3
N= 82 % 34 41.5 21 25.6 7 8.5
1.09 0.75-1.59 1.07 0.62-1.85 1.32 0.49-3.57
0.763 0.807 0.581
Multiparous women - Vaginal Birth not achieved in 24 hours - Caesarean section – all - Caesarean section – fetal distress
N=116 % 27 23.3 13 11.2 5 4.3
N=139 % 35 25.2 18 13.0 10 7.2
0.92 0.60-1.43 0.85 0.44-1.66 0.59 0.21-1.68
0.903 0.693 0.322
Multiparous women, BS 0-3 - Vaginal Birth not achieved in 24 hours - Caesarean section – all - Caesarean section – fetal distress
N= 75 % 18 24.0 10 13.3 4 5.3
N= 84 % 25 29.8 13 15.5 7 8.3
0.81 0.48-1.36 0.86 0.40-1.85 0.64 0.20-2.10
0.492 0.701 0.457
Multiparous women, BS 4-6 - Vaginal Birth not achieved in 24 hours - Caesarean section – all - Caesarean section – fetal distress
N= 41 % 9 22.0 3 7.3 1 2.4
N= 55 % 10 18.2 5 9.2 3 5.5
1.21 0.54-2.70 0.80 0.20-3.18 0.45 0.05-4.15
0.399 0.756 0.465
Statistically significant results (p<0.05) in bold text.
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect.
104
5.4(3) Time of Commencing Induction - Secondary Outcomes:
Evidence of Effect
The likelihood of a woman having a Bishop’s score of less than seven 24 hours after the
induction commenced (Morning admission 35/280 (12.5%) versus Evening admission
41/340 (12.1%); RR 1.04 95% CI 0.68-1.58; p=0.503), requiring further doses of known
vaginal PGE2 gel (Morning admission 43/280 (15.4%) versus Evening admission
51/340 (15.0%); RR 0.98 95% CI 0.68-1.42; p=0.915), or the induction to birth interval
(Morning admission median interval 18.9 hours (interquartile range 6.2-31.6) versus
Evening admission median interval 21.0 hours (interquartile range 9.5-32.5); p=0.145)
did not differ between women admitted in the morning when compared with women
admitted in the evening (Table 5.4(3)).
Women admitted in the morning were significantly less likely to require oxytocin
infusion when compared with women admitted for induction in the evening (Morning
admission 126/280 (45.0%) versus Evening admission 184/340 (54.1%); RR 0.83 95%
CI 0.70-0.97; p=0.022). This effect was also present for women admitted in the morning
who received vaginal PGE2 gel as the induction agent (Morning admission 54/142
(38.0%) versus Evening admission 91/173 (52.6%); RR 0.73 95% CI 0.56-0.93;
p=0.012), but not for those women who received misoprostol as the induction agent
(Morning admission 72/138 (52.2%) versus Evening admission 93/167 (55.7%); RR
0.93 95% CI 0.75-1.15; p=0.497). Women with an initial Bishop’s score of 0-3 admitted
in the morning were less likely to require oxytocin infusion (Morning admission 80/177
(45.2%) versus Evening admission 115/203 (56.7%); RR 0.80 95% CI 0.65-0.98;
p=0.026) and had a shorter induction to birth interval (Morning admission median
interval 19.3 hours (interquartile range 6.3-32.3) versus Evening admission median
interval 22.8 hours (interquartile range 10.9-34.7); p=0.043) when compared with
women who were admitted in the evening. Nulliparous women admitted in the morning
were less likely to require oxytocin infusion than women admitted in the evening
(Morning admission 92/164 (56.1%) versus Evening admission 135/201 (67.2%); RR
0.83 95% CI 0.70-0.98; p=0.029), as were nulliparous women with an initial Bishop’s
score of 0-3 who were admitted in the morning (Morning admission 59/102 (57.8%)
versus Evening admission 84/119 (70.6%); RR 0.82 95% CI 0.67-1.00; p=0.048), who
also had a significantly shorter induction to birth interval (Morning admission median
105
interval 23.3 hours (interquartile range 9.2-37.4) versus Evening admission median
interval 25.5 hours (interquartile range 14.9-36.1); p=0.042).
There were no other differences identified related to the time of admission for induction
of labour and induction agent used, maternal parity, and initial Bishop’s score.
Table 5.4(3) Time of Commencing Induction - Secondary Outcomes:
Evidence of Effect
Morning Admission Evening Admission Treatment Effect RR 95%CI
P value
All women - Bishop’s Score <7 after 24 hours - Further doses of known PGE2- Oxytocin infusion - Induction to birth interval*
N=280 % 35 12.5 43 15.4 126 45.0 18.9 6.2-31.6
N=340 % 41 12.1 51 15.0 184 54.1 21.0 9.5-32.5
1.04 0.68-1.58 0.98 0.68-1.42 0.83 0.70-0.97
0.503 0.915 0.022 0.145
Misoprostol - Bishop’s score <7 after 24 hours - Further doses of known PGE2- Oxytocin infusion - Induction to birth interval*
N=138 % 21 15.2 27 19.6 72 52.2 20.7 7.6-33.8
N=167 % 26 15.6 31 18.6 93 55.7 21.6 9.6-33.6
0.98 0.58-1.66 0.99 0.63-1.57 0.93 0.75-1.15
0.938 0.978 0.497 0.862
Vaginal PGE2- Bishop’s score <7 after 24 hours - Further doses of known PGE2
- Oxytocin infusion - Induction to birth interval*
N=142 % 14 9.9 16 11.3 54 38.0 16.9 5.4-28.4
N=173 % 15 8.9 20 11.6 91 52.6 20.0 8.9-31.1
1.14 0.57-2.28 0.95 0.52-1.75 0.72 0.56-0.93
0.354 0.871 0.012 0.080
Bishop’s score 0-3 - Bishop’s score <7 after 24 hours - Further doses of known PGE2
- Oxytocin infusion - Induction to birth interval*
N=177 % 27 15.3 32 18.1 80 45.2 19.3 6.3-32.3
N=203 % 34 16.8 43 21.2 115 56.7 22.8 10.9-34.7
0.91 0.57-1.45 0.85 0.57-1.29 0.80 0.65-0.98
0.572 0.448 0.026 0.043
Bishop’s score 4-6 - Bishop’s score <7 after 24 hours - Further doses of known PGE2
- Oxytocin infusion - Induction to birth interval*
N=103 % 8 7.8 11 10.7 46 44.7 18.7 6.4-31.0
N=137 % 7 5.1 8 5.8 69 50.4 17.7 6.3-29.1
1.92 0.72-5.14 1.83 0.76-4.38 0.89 0.68-1.16
0.541 0.169 0.381 0.941
Nulliparous women - Bishop’s Score <7 after 24 hours - Further doses of known PGE2
- Oxytocin infusion - Induction to birth interval*
N=164 % 24 21.6 30 18.3 92 56.1 21.4 8.9-33.9
N=201 % 34 16.9 38 18.9 135 67.2 23.5 12.7-34.3
0.87 0.54- 1.40 0.93 0.61- 1.42 0.83 0.70- 0.98
0.986 0.734 0.029 0.153
Nulliparous women, BS 0-3 - Bishop’s Score <7 after 24 hours - Further doses of known PGE2
- Oxytocin infusion - Induction to birth interval*
N=102 % 19 18.6 22 21.6 59 57.8 23.3 9.2-37.4
N=119 % 27 22.7 31 26.1 84 70.6 25.5 14.9-36.1
0.82 0.49-1.39 0.83 0.51-1.34 0.82 0.67-1.00
0.890 0.437 0.048 0.042
Nulliparous women, BS 4-6 - Bishop’s Score <7 after 24 hours - Further doses of known PGE2- Oxytocin infusion - Induction to birth interval*
N= 62 % 5 8.1 8 12.9 33 53.2 20.7 9.7-31.7
N= 82 % 7 8.5 7 8.5 51 62.2 21.3 11.7-30.9
0.94 0.31-2.84 1.51 0.58-3.94 0.86 0.64-1.14
0.901 0.396 0.280 0.842
106
Morning Admission Evening Admission Treatment Effect RR 95%CI
P value
Multiparous women - Bishop’s Score <7 after 24 hours - Further doses of known PGE2- Oxytocin infusion - Induction to birth interval*
N=116 % 11 9.5 13 11.2 34 29.3 15.3 6.5-24.1
N=139 % 7 5.0 13 9.4 49 35.3 16.6 5.1-28.1
1.88 0.75-4.70 1.14 0.55-2.35 0.83 0.58-1.19
0.204 0.718 0.300 0.955
Multiparous women, BS 0-3 - Bishop’s Score <7 after 24 hours - Further doses of known PGE2- Oxytocin infusion - Induction to birth interval*
N= 75 % 8 10.7 10 13.3 21 28.0 16.3 8.6-24.0
N= 84 % 7 8.3 12 14.3 31 36.9 18.0 5.7-30.3
1.28 0.49-3.36 0.93 0.43-2.03 0.76 0.48-1.20
0.391 0.862 0.232 0.686
Multiparous women, BS 4-6 - Bishop’s Score <7 after 24 hours - Further doses of known PGE2- Oxytocin infusion - Induction to birth interval*
N= 41 % 3 7.3 3 7.3 13 31.7 14.3 4.2-24.4
N= 55 % 0 0.0 1 1.8 18 32.7 15.4 6.1-24.7
9.33 0.50-175.86 4.02 0.43- 37.30 0.97 0.54- 1.74
0.091 0.182 0.916 0.833
Statistically significant results (p<0.05) in bold text.
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect.
* Median and interquartile range (interval in hours); Wilcoxon Rank Sum Test
BS = Bishop’s Score
PGE2 = vaginal prostaglandin E2 gel
5.4(4) Time of Commencing Induction – Secondary Outcomes: Labour
and Birth Complications
The occurrence of uterine hyperstimulation syndrome without associated fetal heart rate
changes (Morning admission 10/280 (3.6%) versus Evening admission 7/340 (2.1%);
RR 1.73 95% CI 0.67-4.48; p=0.260), need for any analgesia (Morning admission
259/280 (92.5%) versus Evening admission 324/340 (95.3%); RR 0.97 95% CI 0.93-
1.01; p=0.140) or need for epidural analgesia (Morning admission 190/280 (67.9%)
versus Evening admission 209/340 (61.5%); RR 1.10 95% CI 0.98-1.23; p=0.117) was
not significantly different for women admitted in the morning compared with women
admitted in the evening (Table 5.4(4)). The presence of meconium stained liquor
(Morning admission 42/280 (15.0%) versus Evening admission 51/340 (15.0%); RR
0.99 95% CI 0.68-1.44; p=0.962), instrumental vaginal birth (Morning admission
47/280 (16.8%) versus Evening admission 62/340 (18.2%); RR 0.92 95% CI 0.65-1.30;
p=0.636), and length of labour (Morning admission mean interval 7.2 hours (standard
deviation 4.1) versus Evening admission mean interval 7.4 hours (standard deviation
107
4.2); p=0.555) was not different between morning and evening admission for induction
to start. The number of women with blood loss greater than 600mL (Morning admission
55/280 (19.6%) versus Evening admission 56/340 (16.5%); RR 1.19 95% CI 0.85-1.67;
p=0.307), greater than 1000mL (Morning admission 11/280 (3.9%) versus Evening
admission 16/340 (4.7%); RR 0.83 95% CI 0.39-1.76; p=0.627), or needing blood
transfusion (Morning admission 6/280 (2.1%) versus Evening admission 8/340 (2.4%);
RR 0.91 95% CI 0.32-2.59; p=0.856) did not differ between morning and evening
admission.
Women with an initial Bishop’s score of 4-6 (Morning admission 12/103 (11.7%)
versus Evening admission 31/137 (22.6%); RR 0.51 95% CI 0.28-0.95; p=0.028) and in
particular nulliparous women with an initial Bishop’s score of 4-6 (Morning admission
10/62 (16.1%) versus Evening admission 28/82 (34.2%); RR 0.47 95% CI 0.25-0.90;
p=0.015) were less likely to require instrumental vaginal birth when admission occurred
in the morning compared with the evening. There were no other effects identified
between time of starting the induction process and the induction agent used
(misoprostol versus vaginal PGE2 gel), maternal parity (nulliparous versus
multiparous), or initial Bishop’s score (Bishop’s score 0-3 versus Bishop’s score 4-6)
for labour and birth complications.
Table 5.4(4) Time of Commencing Induction – Secondary Outcomes:
Labour and Birth Complications
Morning Admission Evening Admission Treatment Effect RR 95% CI
P value
All women - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=280 % 10 3.6 0 0.0 259 92.5 190 67.9 42 15.0 7.2 4.1 47 16.8 55 19.6 11 3.9 6 2.1
N=340 % 7 2.1 0 0.0 324 95.3 209 61.5 51 15.0 7.4 4.2 62 18.2 56 16.5 16 4.7 8 2.4
1.73 0.67- 4.48 Not estimable 0.97 0.93- 1.01 1.10 0.98- 1.23 0.99 0.68- 1.44 0.92 0.65- 1.30 1.19 0.85- 1.67 0.83 0.39- 1.76 0.91 0.32- 2.59
0.260 0.140 0.117 0.962 0.555 0.636 0.307 0.627 0.856
108
Morning Admission Evening Admission Treatment Effect RR 95% CI
P value
Misoprostol - Uterine HSS – no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=138 % 1 0.7 0 0.0 133 96.4 101 73.2 25 18.1 7.7 4.2 28 20.3 22 15.9 3 2.2 0 0.0
N=167 % 2 1.2 0 0.0 162 97.0 108 64.7 25 15.0 7.7 4.2 30 18.0 25 15.0 10 6.0 7 4.2
0.60 0.05- 6.53 Not estimable 0.99 0.95- 1.03 1.12 0.97- 1.31 1.20 0.73- 2.00 1.13 0.71- 1.79 1.06 0.63- 1.80 0.36 0.10- 1.29 0.08 0.00- 1.40
0.673 0.717 0.132 0.472 0.938 0.607 0.826 0.101 0.151
Vaginal PGE2- Uterine HSS – no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=142 % 9 6.3 0 0.0 126 88.7 89 62.7 17 12.0 6.7 3.9 19 13.4 33 23 2 8 5.6 6 4.2
N=173 % 5 2.9 0 0.0 162 93.6 101 58.4 26 15.0 7.1 4.1 32 18.5 31 17.9 6 3.5 1 0.6
2.19 0.75- 6.40 Not estimable 0.95 0.88- 1.02 1.07 0.90- 1.28 0.79 0.44- 1.39 0.72 0.43- 1.22 1.30 0.84- 2.01 1.62 0.58- 4.57 7.31 0.89-60.01
0.151 0.131 0.449 0.408 0.423 0.224 0.242 0.353 0.289
Bishop’s Score 0-3 - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=177 % 8 4.5 0 0.0 165 93.2 122 68.9 28 15.8 7.2 4.1 35 19.8 37 20.9 9 5.1 5 2.8
N=203 % 3 1.5 0 0.0 195 96.1 131 64.5 34 16.8 7.6 4.1 31 15.3 32 15.8 9 4.4 4 2.0
3.06 0.82-11.35 Not estimable 0.97 0.92- 1.02 1.07 0.93- 1.23 0.94 0.60- 1.49 1.29 0.83- 2.01 1.33 0.86- 2.03 1.15 0.47- 2.83 1.43 0.39- 5.26
0.078 0.216 0.365 0.807 0.433 0.248 0.195 0.766 0.585
Bishop’s Score 4-6 - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=103 % 2 1.9 0 0.0 94 91.3 68 66.0 14 13.6 7.1 4.2 12 11.7 18 17.5 2 1.9 1 1.0
N=137 % 4 2.9 0 0.0 129 94.2 78 56.9 17 12.4 7.1 4.3 31 22.6 24 17.5 7 5.1 4 2.9
0.67 0.12- 3.56 Not estimable 0.97 0.90- 1.04 1.16 0.95- 1.42 1.10 0.57- 2.12 0.51 0.28- 0.95 1.00 0.57- 1.74 0.38 0.08- 1.79 0.33 0.04- 2.93
0.631 0.386 0.154 0.787 0.941 0.028 0.993 0.201 0.295
Nulliparous women - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=164 % 8 4.9 0 0.0 157 95.7 125 76.2 28 17.1 8.9 4.2 40 24.4 40 24.4 6 3.7 4 2.4
N=201 % 6 3.0 0 0.0 198 98.5 140 69.7 32 15.9 9.1 4.3 50 24.9 39 19.4 10 5.0 4 2.0
1.63 0.58- 4.60 Not estimable 0.97 0.94- 1.01 1.08 0.96- 1.23 1.06 0.67- 1.69 0.98 0.68- 1.41 1.26 0.85- 1.85 0.73 0.27- 1.97 1.22 0.31- 4.81
0.356 0.124 0.206 0.795 0.617 0.908 0.253 0.533 0.776
Nulliparous women, BS 0-3 - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=102 % 6 5.9 0 0.0 97 95.1 77 75.5 19 18.6 9.1 4.2 30 29.4 26 25.5 4 3.9 3 2.9
N=119 % 2 1.7 0 0.0 117 98.3 87 73.1 22 18.5 9.7 4.1 22 18.5 24 20.2 7 5.9 4 3.4
3.50 0.72-16.96 Not estimable 0.97 0.92- 1.02 1.03 0.88- 1.21 1.01 0.58- 1.75 1.59 0.98- 1.02 1.26 0.78- 2.06 0.67 0.20- 2.21 0.88 0.20- 3.82
0.096 0.173 0.687 0.979 0.393 0.057 0.346 0.504 0.859
109
Morning Admission Evening Admission Treatment Effect RR 95% CI
P value
Nulliparous women, BS 4-6 - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N= 62 % 2 3.2 0 0.0 60 96.8 48 77.4 9 14.5 8.5 4.2 10 16.1 14 22.6 2 3.2 1 1.6
N= 82 % 4 4.9 0 0.0 81 98.8 53 64.6 10 12.2 8.5 4.4 28 34.2 15 18.3 3 3.7 0 0.0
0.66 0.13- 3.50 Not estimable 0.98 0.93- 1.03 1.20 0.97- 1.48 1.19 0.51- 2.75 0.47 0.25- 0.90 1.23 0.64- 2.36 0.88 0.15- 5.12 3.95 0.16-95.41
0.623 0.404 0.097 0.684 0.986 0.015 0.525 0.888 0.249
Multiparous women - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N=116 % 2 1.7 0 0.0 102 87.9 65 56.0 14 12.1 5.3 3.1 7 6.0 15 12.9 5 4.3 2 1.7
N=139 % 1 0.7 0 0.0 126 90.7 69 49.6 19 13.7 5.6 3.2 12 8.6 17 12.2 6 4.3 4 2.9
2.38 0.22- 25.96 Not estimable 0.97 0.89- 1.06 1.13 0.89- 1.42 0.87 0.46- 1.66 0.70 0.28- 1.72 1.06 0.55- 2.02 1.00 0.31- 3.18 0.60 0.11- 3.21
0.476 0.487 0.313 0.681 0.528 0.437 0.868 0.994 0.548
Multiparous women, BS 0-3 - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N= 75 % 2 2.7 0 0.0 68 90.7 45 60.0 9 12.0 5.2 2.8 5 6.7 11 14.7 5 6.7 2 2.7
N= 84 % 1 1.2 0 0.0 78 92.9 44 52.4 12 14.3 5.6 3.0 9 10.7 8 9.5 2 2.4 0 0.0
2.24 0.21- 24.20 Not estimable 0.98 0.89- 1.07 1.15 0.87- 1.51 0.84 0.38- 1.88 0.62 0.22- 1.77 1.54 0.65- 3.62 2.80 0.56- 14.01 5.59 0.27-114.66
0.495 0.615 0.334 0.671 0.445 0.369 0.318 0.189 0.132
Multiparous women, BS 4-6 - Uterine HSS - no FHR changes - Uterine rupture - Need for any analgesia - Need for epidural - Meconium stained liquor - Length of labour* - Instrumental vaginal birth - Blood loss >600mL - Blood loss >1000mL - Need for blood transfusion
N= 41 % 0 0.0 0 0.0 34 82.9 20 48.8 5 12.2 5.4 3.5 2 4.9 4 9.8 0 0.0 0 0.0
N= 55 % 0 0.0 0 0.0 48 87.3 25 45.5 7 12.7 5.5 3.5 3 5.5 9 16.4 4 7.3 4 7.3
Not estimable Not estimable 0.95 0.80- 1.13 1.07 0.70- 1.64 0.96 0.33- 2.80 0.89 0.16- 5.11 0.60 0.20- 1.80 0.15 0.01- 2.68 0.15 0.01- 2.68
0.551 0.747 0.938 0.921 0.900 0.349 0.078 0.078
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect. Statistically significant results (p<0.05) in bold text.
* Mean and standard deviation (interval in hours); Student’s T-Test
HSS = hyperstimulation syndrome
FHR = fetal heart rate
110
5.4(5) Time of Commencing Induction – Secondary Outcomes:
Neonatal Complications
The number of infants with birth weight less than 2.5kg (Morning admission 8/280
(2.9%) versus Evening admission 11/340 (3.2%); RR 0.85 95% CI 0.35-2.09; p=0.731),
Apgar score of less than seven at five minutes of age (Morning admission 1/280 (0.4%)
versus Evening admission 6/340 (1.8%); RR 0.34 95% CI 0.05-2.17; p=0.101), cord pH
of less than 7.18 (Morning admission 13/280 (11.8%) versus Evening admission 13/340
(9.4%); RR 1.20 95% CI 0.58-2.49; p=0.618), or admission to the neonatal intensive
care unit (Morning admission 1/280 (0.4%) versus Evening admission 3/340 (0.8%);
RR 0.60 95% CI 0.08-4.61; p=0.426) did not differ between morning and evening
admission to start induction of labour (Table 5.4(5)). There were no infants with
neonatal encephalopathy, and no infant deaths to 28 days of life.
There were no differential effects in outcomes related to the induction agent used
(misoprostol versus vaginal PGE2 gel), maternal parity (nulliparous versus
multiparous), or initial Bishop’s score (Bishop’s score 0-3 versus Bishop’s score 4-6),
and the time of admission for induction.
Table 5.4(5) Time of Commencing Induction – Secondary Outcomes:
Neonatal Complications
Morning Admission Evening Admission Treatment Effect RR 95% CI
P value
All infants - Birth-weight <2.5kg - Apgar <7 @ 5 minutes - Cord pH <7.18 - NICU admission - Neonatal encephalopathy - Postnatal death*
N=280 % 8 2.9 1 0.4 13 11.8 1 0.4 0 0.0 0 0.0
N=340 % 11 3.2 6 1.8 13 9.4 3 0.8 0 0.0 0 0.0
0.85 0.35- 2.09 0.34 0.05- 2.17 1.20 0.58- 2.49 0.60 0.08- 4.61 Not estimable Not estimable
0.731 0.101 0.618 0.426
Misoprostol - Birth-weight <2.5kg - Apgar <7 @ 5 minutes - Cord pH<7.18 - NICU admission - Neonatal encephalopathy - Postnatal death*
N=138 % 5 3.6 0 0.0 4 7.3 0 0.0 0 0.0 0 0.0
N=167 % 7 4.2 2 1.2 6 10.3 2 1.2 0 0.0 0 0.0
0.82 0.27- 2.51 0.24 0.01- 4.99 0.65 0.19- 2.18 0.24 0.01- 4.99 Not estimable Not estimable
0.724 0.197 0.487 0.197
111
Morning Admission Evening Admission Treatment Effect RR 95% CI
P value
Vaginal PGE2- Birth-weight <2.5kg - Apgar <7 @ 5 minutes - Cord pH <7.18 - NICU admission - Neonatal encephalopathy - Postnatal death*
N=142 % 3 2.1 1 0.7 9 16.4 1 0.7 0 0.0 0 0.0
N=173 % 4 2.3 4 2.3 7 8.8 1 0.6 0 0.0 0 0.0
0.91 0.21- 3.97 0.30 0.03- 2.69 1.85 0.74- 4.65 1.21 0.08-19.31 Not estimable Not estimable
0.898 0.256 0.190 0.888
Statistically significant results (p<0.05) in bold text.
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect.
*Neonatal Death = death of a live-born infant within 28 days of birth
NICU = neonatal intensive care unit
5.4(6) Time of Commencing Induction – Secondary Outcomes:
Maternal Complications
The likelihood of any maternal side effect (Morning admission 75/280 (26.8%) versus
Evening admission 75/340 (22.3%); RR 1.21 95% CI 0.92-1.60; p=0.182), nausea
(Morning admission 20/280 (7.1%) versus Evening admission 26/340 (7.7%); RR 0.93
95% CI 0.53-1.64; p=0.813), vomiting (Morning admission 6/280 (2.1%) versus
Evening admission 8/340 (2.4%); RR 0.92 95% CI 0.32-2.62; p=0.877), diarrhoea
(Morning admission 7/280 (2.5%) versus Evening admission 7/340 (2.1%); RR 1.18
95% CI 0.42-3.32; p=0.753), or flushing (Morning admission 4/280 (1.4%) versus
Evening admission 5/340 (1.5%); RR 0.83 95% CI 0.20-3.50; p=0.936) did not differ
for women admitted in the morning and women admitted in the evening (Table 5.4(6)).
There were no women admitted to intensive care, no cases of hyperpyrexia or coma,
and no maternal deaths. There were no differential effects in outcomes related to the
induction agent used (misoprostol versus vaginal PGE2 gel), maternal parity
(nulliparous versus multiparous), or initial Bishop’s score (Bishop’s score 0-3 versus
Bishop’s score 4-6) and the time of admission for induction.
112
Table 5.4(6) Time of Commencing Induction – Secondary Outcomes:
Maternal Complications
Morning Admission Evening Admission Treatment Effect RR 95% CI
P value
All women - Any side effect - Nausea - Vomiting - Diarrhoea - Flushing - Intensive care unit admission - Hyperpyrexia - Coma - Maternal death
N=280 % 75 26.8 20 7.1 6 2.1 7 2.5 4 1.4 0 0.0 0 0.0 0 0.0 0 0.0
N=340 % 75 22.3 26 7.7 8 2.4 7 2.1 5 1.5 0 0.0 0 0.0 0 0.0 0 0.0
1.21 0.92- 1.60 0.93 0.53- 1.64 0.92 0.32- 2.62 1.18 0.42- 3.32 0.84 0.20- 3.50 Not estimable Not estimable Not estimable Not estimable
0.182 0.813 0.877 0.753 0.936
Misoprostol - Any side effect - Nausea - Vomiting - Diarrhoea - Flushing
N=138 % 32 23.2 8 5.8 1 0.7 3 2.2 2 1.5
N=167 % 31 18.6 9 5.4 3 1.8 2 1.2 3 1.8
1.23 0.80- 1.91 1.07 0.43- 2.71 0.41 0.04- 3.91 1.74 0.30-10.25 0.81 0.14- 4.77
0.347 0.880 0.439 0.541 0.812
Vaginal PGE2 - Any side effect - Nausea - Vomiting - Diarrhoea - Flushing
N=142 % 43 30.3 12 8.5 5 3.5 4 2.8 2 1.4
N=173 % 44 25.4 17 9.8 5 2.9 5 2.9 2 1.2
1.19 0.84- 1.70 0.86 0.42- 1.74 1.22 0.36- 4.12 0.96 0.26- 3.50 1.22 0.17- 8.54
0.332 0.673 0.752 0.950 0.842
Statistically significant results (p<0.05) in bold text.
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect.
5.4(7) Time of Commencing Induction – Women’s Satisfaction and
Preferences for Care at Discharge
All 620 women for whom satisfaction questionnaires were available, were satisfied with
the care that they received (Table 5.4(7)). The number of women who were not satisfied
(defined as either not at all satisfied or only mildly satisfied) with their induction were
similar between the morning admission group and the evening admission group
(Morning admission 56/280 (20.0%) versus Evening admission 59/340 (17.4%); RR
1.15 95% CI 0.82-1.59; p=0.418), as were those unsatisfied with their labour (Morning
admission 54/280 (19.3%) versus Evening admission 82/340 (24.2%); RR 0.79 95% CI
0.58-1.08; p=0.136) and birth (Morning admission 33/280 (11.8%) versus Evening
admission 53/340 (15.6%); RR 0.76 95% CI 0.51-1.14; p=0.192). Overall, 75.2% of
women, given similar circumstances, would participate in the study again, and 83.1% of
women would recommend a friend in similar circumstances participate in the study,
113
figures that were not significantly different between the morning and evening admission
groups.
Table 5.4(7) Time of Commencing Induction of Labour – Women’s
Satisfaction and Preferences for Care at Discharge
Morning Admission
Evening Admission
Treatment Effect RR 95% CI
P value
All women - Woman not satisfied with care - Not satisfied with IOL - Not satisfied with labour - Not satisfied with birth - Participate in study again - Recommend others participate in study
N=280 % 0 0.0 56 20.0 54 19.3 33 11.8 216 77.1 238 85.0
N=340 % 0 0.0 59 17.4 82 24.2 53 15.6 250 73.5 277 81.5
Not estimable 1.15 0.82-1.59 0.79 0.58-1.08 0.76 0.51-1.14 1.05 0.96-1.15 1.04 0.97-1.11
0.418 0.136 0.192 0.291 0.310
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect.
Statistically significant results (p<0.05) in bold text.
IOL = induction of labour
5.4(8) Time of Commencing Induction - Women’s Likes and Dislikes at
Discharge
Overall, women’s responses to their participation in the trial were positive, with 28.1%
indicating that they “liked being involved in the study”, and 32.3% indicating that they
“liked everything” during their induction and labour (Table 5.4(8)). Few women (1.9%)
indicated that they “disliked being involved in the study”, or that they “didn’t like
anything” during their induction and labour (8.7%), responses that did not differ for
women in the morning admission group when compared with those in the evening
admission group (Table 5.4(8)). Women liked the “reassurance that (their) baby was
well” (58.9%), while 16.6% of women indicated that they didn’t like having their baby
monitored. Again, these responses were not different between women in the morning
admission group and those in the evening admission group. While 37.4% of women
indicated that they had no side effects from the medication, and 10.0% few medication
side effects, 19.8% of women disliked abdominal cramps, 13.7% disliked nausea or
vomiting, 5.2% disliked hot flushes, 3.9% disliked headaches, and 1.9% disliked
114
diarrhoea. There were no differences in these responses between women in the morning
admission group and those in the evening admission group.
Fewer women in the morning admission group indicated a lack of sleep to be a dislike
during induction of labour when compared with women in the evening admission group
(Morning admission 1/280 (0.4%) versus Evening admission 15/340 (4.4%); RR 0.08
95% CI 0.01-0.61; p=0.015).
Table 5.4(8) Time of Commencing Induction - Women’s Likes and
Dislikes at Discharge
Morning Admission
Evening Admission
Treatment Effect RR 95% CI
P value
All women I Liked… - Didn’t like anything - No side effects from medication - Few side effects from medication - Reassurance baby was well - Being involved in this study
N=280 % 19 9.6 97 34.6 33 11.8 166 59.3 88 31.4
N=340 % 35 10.3 135 39.7 29 8.5
199 58.5 86 25.3
0.66 0.39-1.13 0.87 0.71-1.07 1.38 0.86-2.22 1.01 0.89-1.16 1.25 0.97-1.61
0.127 0.188 0.180 0.845 0.082
I Disliked… - Like everything - Nausea or vomiting - Diarrhoea - Abdominal cramps - Headaches - Hot flushes - Too many internal examinations - Having the baby monitored - Being involved in this study - Lack of sleep
99 35.4 36 12.9 7 2.5 47 16.8 12 4.3 13 4.6 73 26.1 39 13.9 6 2.1 1 0.4
101 29.7 49 14.4 5 1.5 76 22.4 12 3.5 19 5.6 99 29.1 64 18.8 9 2.7 15 4.4
1.20 0.96-1.51 0.90 0.60-1.34 1.71 0.55-5.33 0.75 0.54-1.04 1.21 0.55-2.66 0.83 0.42-1.66 0.87 0.67-1.12 0.74 0.51-1.07 0.82 0.30-2.28 0.08 0.01-0.61
0.116 0.590 0.356 0.083 0.629 0.601 0.285 0.107 0.702 0.015
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect.
Statistically significant results (p<0.05) in bold text.
115
5.4(9) Time of Commencing Induction – Women’s Satisfaction and
Preferences for Care at 6 weeks Postpartum
All 617 (99.5%) women for whom satisfaction questionnaires were available, were
satisfied with the care that they received (Table 5.4(9)). The number of women who
were not satisfied (defined as either not at all satisfied or only mildly satisfied) with
their induction were similar between the morning admission group and the evening
admission group (Morning admission 60/278 (21.6%) versus Evening admission 77/339
(22.7%); RR 0.94 95% CI 0.70-1.26; p=0.674), as were those unsatisfied with their
labour (Morning admission 60/278 (21.6%) versus Evening admission 80/339 (23.6%);
RR 0.90 95% CI 0.67-1.21; p=0.495) and birth (Morning admission 18/278 (6.5%)
versus Evening admission 26/339 (7.7%); RR 0.91 95% CI 0.61-1.36; p=0.651).
Overall, 71.0% of women, given similar circumstances, would participate in the study
again, and 80.2% of women would recommend a friend in similar circumstances
participate in the study, figures that were not significantly different between the
morning and evening admission groups.
Table 5.4(9) Time of Commencing Induction – Women’s Satisfaction
and Preferences for Care at 6 weeks Postpartum
Morning Admission
Evening Admission
Treatment Effect RR 95% CI
P value
All women - Woman not satisfied with care - Not satisfied with IOL - Not satisfied with labour - Not satisfied with birth - Participate in study again - Recommend others participate in study
N=278 % 0 0.0 60 21.6 60 21.6 18 6.5 202 72.7 231 83.1
N=339 % 0 0.0 77 22.7 80 23.6 26 7.7 236 69.6 264 77.9
Not estimable 0.94 0.70-1.26 0.90 0.67-1.21 0.91 0.61-1.36 1.04 0.94-1.15 1.07 0.99-1.15
0.674 0.495 0.651 0.465 0.105
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect. Statistically significant results (p<0.05) in bold text.
IOL = induction of labour
116
5.4(10) Time of Commencing Induction - Women’s Likes and Dislikes
at 6 weeks Postpartum
Overall, women’s responses to their participation in the trial were positive, with 31.4%
indicating that they “liked being involved in the study”, and 30.6% indicating that they
“liked everything” during their induction and labour (Table 5.4(10)). Few women
(5.5%) indicated that they “disliked being involved in the study”, or that they “didn’t
like anything” during their induction and labour (9.9%), responses that did not differ for
women in the morning admission group when compared with those in the evening
admission group (Table 5.4(10)). Women liked the “reassurance that (their) baby was
well” (61.3%), while 16.7% of women indicated that they didn’t like having their baby
monitored. Again, these responses were not different between women in the morning
admission group and those in the evening admission group. While 44.2% of women
indicated that they had no side effects from the medication, and 8.1% few medication
side effects, 17.0% of women disliked abdominal cramps, 13.6% disliked nausea or
vomiting, 4.5% disliked headaches, 3.9% disliked hot flushes, and 1.8% disliked
diarrhoea. There were no differences in these responses between women in the morning
admission group and those in the evening admission group.
Fewer women in the morning admission group indicated a lack of sleep to be a dislike
during induction of labour when compared with women in the evening admission group
(Morning admission 0/278 (0.0%) versus Evening admission 12/339 (3.5%); RR 0.10
95% CI 0.01-0.76; p=0.002).
117
Table 5.4(10) Time of Commencing Induction - Women’s Likes and
Dislikes at 6 weeks Postpartum
Morning Admission
Evening Admission
Treatment Effect RR 95% CI
P value
All women I Liked… - Didn’t like anything - No side effects from medication - Few side effects from medication - Reassurance baby was well - Being involved in this study
N=278 % 26 9.4 120 43.2 24 8.6 168 60.4 84 30.2
N=339 % 35 9.4 153 45.1 26 7.7
210 61.9 110 32.4
0.98 0.60-1.60 0.95 0.80-1.14 1.13 0.66-1.92 0.97 0.86-1.10 0.93 0.73-1.17
0.923 0.599 0.662 0.655 0.531
I Disliked… - Like everything - Nausea or vomiting - Diarrhoea - Abdominal cramps - Headaches - Hot flushes - Too many internal examinations - Having the baby monitored - Being involved in this study - Lack of sleep
94 33.8 38 13.7 7 2.5 42 15.1 9 3.2 11 4.0 86 30.9 42 15.1 13 4.7 0 0.0
95 28.0 46 13.6 4 1.2 63 18.6 19 5.6 13 3.8 97 28.6 61 18.0 21 6.2 12 3.5
1.22 0.96-1.55 1.00 0.67-1.50 2.09 0.62-7.07 0.81 0.57-1.16 0.58 0.27-1.26 1.02 0.46-2.23 1.06 0.84-1.36 0.84 0.58-1.20 0.74 0.38-1.46 0.10 0.01-0.76
0.100 0.990 0.236 0.250 0.166 0.969 0.615 0.326 0.387 0.002
Figures are numbers and percentages with relative risk (RR) and 95% Confidence
Intervals (CI) as treatment effect.
Statistically significant results (p<0.05) in bold text.
5.5 DISCUSSION
As far as can be ascertained, this is the first randomised controlled trial that has assessed
the impact of time of commencing induction of labour on maternal and infant outcomes.
Traditionally, women have been admitted to hospital to commence induction of labour
in the evening, in the expectation that birth will occur during daylight hours. This time
of birth may be more convenient for caregivers, and has implications for staffing levels
within maternity units. However, this is in contrast to the well documented diurnal
variation in onset of labour, which consistently demonstrate a peak onset of labour in
the evening and early hours of the morning (Cooperstock 1987; Fraser 1989; Cagnacci
1998; Lindow 2000; Mancuso 2004).
118
Admission and commencing the induction process in the morning was not associated
with any differences in the number of women who did not achieve vaginal birth within
24 hours, uterine hyperstimulation with associated fetal heart rate changes, caesarean
section, or caesarean section for fetal distress, when compared with admission in the
evening.
Women with a Bishop’s score of 0-3 on admission, nulliparous women, and in
particular nulliparous women with a Bishop’s score of 0-3, required less oxytocin
during labour, and had a shorter induction to birth interval when admission occurred in
the morning. However, there were no differences in the length of labour documented.
Women with a Bishop’s score of 4-6 were less likely to require instrumental vaginal
birth when admission occurred in the morning, compared with evening admission, as
were nulliparous women with an initial Bishop’s score of 4-6.
It is unclear if these observations reflect the well-documented physiological diurnal
rhythm in the onset of labour in the evening and early hours of the morning, or if they
are indicative of diurnal variations in clinical practice. With women admitted in the
morning for cervical ripening and induction, the onset of labour would be expected to
occur in the evening. Staffing levels within maternity units tend to be lower in the
evening, and there may be a general reluctance to actively manage labour at this time,
indicated by fewer women receiving an oxytocin infusion when admitted in the
morning. Conversely, women admitted for induction in the evening would be expected
to labour during daylight hours, a time when midwifery staffing levels are greater.
During this time there is greater availability of both junior and consultant medical staff,
and in this setting, the increased use of oxytocin and assisted vaginal birth may reflect a
degree of impatience and pressure to have women birth at a time more convenient for
caregivers.
While there were no significant differences identified in other labour and birth
outcomes between morning and evening admission for induction, there was a trend to a
reduction in the occurrence of major postpartum haemorrhage (defined as blood loss
greater than 1000mL), and need for blood transfusion when admission occurred in the
morning. These findings are consistent with the increased use of oxytocin in women
admitted in the evening. While the overall number of women with blood loss greater
119
than 600mL is high at almost 18%, women requiring induction of labour are recognised
to be at increased risk of obstetric haemorrhage. Furthermore, the rate includes women
with caesarean birth, where the average blood loss is greater than that associated with
vaginal birth.
For the rare, but serious neonatal complications, such as death and neonatal acidosis, the
study was under-powered to detect all but large differences between time of starting
induction of labour. While there is a recognised risk of adverse neonatal outcome
associated with birth during the evening and night (Chalmers 1998; Stewart 1998;
Heller 2000; Luo 2001), it would be necessary to recruit tens of thousands of women
and their infants to assess this adequately in prospective randomised trials, a highly
unlikely scenario to be achieved.
Overall, women were satisfied with the care they received and their induction, labour
and birth. Expression of likes and dislikes during the induction process did not differ
between morning and evening admission, although predictably, more women in the
evening admission group did not like the interruptions to sleep that were associated with
the protocol. However, lack of sleep associated with active labour in the evening was
not identified by women in the morning admission group as a dislike.
5.6 CONCLUSION
Admission in the morning to start induction of labour is advantageous, with fewer
women needing an oxytocin infusion during labour, fewer women requiring
instrumental vaginal birth, and a shorter induction to birth interval when compared with
admission in the evening. While there were no differences in degree of maternal
satisfaction with their induction, labour and birth, more women in the evening
admission group disliked the interruptions overnight and lack of sleep associated with
the trial protocol.
120
Women requiring induction of labour, and particularly nulliparous women should be
offered admission in the morning, rather than the traditional admission in the evening.
This has implications for midwifery and medical staffing levels which currently are
greater during daylight hours.
121
6. COST COMPARISON
6.1 INTRODUCTION There has been a rapid increase in the use of misoprostol in obstetric practice, with
some of this enthusiasm relating to its low cost when compared with other
prostaglandin preparations. The current cost to the Women’s and Children’s Hospital
for a 1mg dose of prostaglandin gel is (Aus)$40.17, with the cost of a 2mg dose
increasing to (Aus)$51.64. The total cost to the hospital for the 1998/1999 financial
year for prostaglandin gel alone was (Aus)$48,307, and for the 1999/2000 financial year
(Aus)$38,508. In contrast a single 200mcg misoprostol tablet costs (Aus)35 cents.
More recent estimates of drug costs from 2001 to the present are not reliable, as the
Women’s and Children’s Hospital met the cost of the drugs for this trial, therefore
influencing the drug budget during this time.
There is an obvious cost differential between misoprostol and vaginal prostaglandin E2
gel relating to drug costs. However, a cost analysis should also take into consideration
other costs to the institution associated with the two methods of induction of labour.
Information derived from the current randomised controlled trial, will be used to detail
the costs associated with each method of induction of labour, with clinical pathways
built into the model.
6.2 STUDY HYPOTHESES
The use of oral misoprostol is associated with
• reduced drug costs, and
• reduced hospitalisation costs.
122
6.3 METHODS
Women were recruited from the Women’s and Children’s Hospital to a randomised
controlled trial comparing oral misoprostol with vaginal PGE2 gel for induction of
labour at term as described previously (Chapter 3). The perspective of the health care
institution was chosen for this analysis, without consideration of the social and
economic costs to the woman and her family.
Costs were specifically compared between oral misoprostol and vaginal prostaglandin
E2 induction of labour, as determined by baseline figures provided by the Women’s and
Children’s Hospital business manager, to obtain a cost per woman induced and a cost
per 100 women induced. Costs were further determined for both nulliparous and
multiparous women with a Bishop’s score at commencement of induction of both zero
to three and four to six (as described in Chapter 3). This involved using the 95%
confidence intervals about the point estimate for the outcomes caesarean birth and
further doses of known vaginal PGE2 gel; the interquartile range about the median for
the outcome induction to birth interval; and the standard deviation about the mean for
the outcome length of labour. Actual doses of trial medication were collected during the
randomised trial.
The costs considered included the drug costs of misoprostol and vaginal PGE2 gel,
midwifery care costs during induction and labour (estimated at the salary of a junior
registered midwife, level 1.9), and hospital derived costs related to caesarean birth and
vaginal birth (Table 6.3(1)). The midwifery care during induction was costed at a rate of
one midwife caring for two women, and care during labour and birth was costed at a
rate of 1.25 midwives caring for a single woman, according to hospital standards. The
hospital derived costs related to vaginal birth and caesarean birth included costs related
to oxytocin infusion, analgesia requirements, operating theatre costs and considered an
average length of hospital stay on the postnatal ward.
123
Table 6.3(1) Costs to the Women’s and Children’s Hospital for
Induction of Labour
Item Cost to WCH 1:2 Midwifery care (per hour) $13.04 per hour 1:1.25 Midwifery care (per hour) $32.60 per hour Misoprostol 35 cents per 200mcg tablet Vaginal PGE2 gel $40.17 per 1mg dose
$51.64 per 2mg dose Vaginal birth (including average length of hospital stay)
$3,973.83
Caesarean birth (including average length of hospital stay)
$6,349.97
6.4 RESULTS
The cost per woman induced with misoprostol was $4,948.61, compared with $5,059.64
per woman induced with vaginal PGE2 gel, a difference of $110.83 per woman induced
in favour of misoprostol (range $15.88 to $121.87) (Table 6.4(1)). For nulliparous
women with an initial Bishop’s score of 0-3, the cost per induction with misoprostol
was $5,331.42, compared with $5,533.84 per induction with vaginal PGE2 gel, a
difference of $202.42 in favour of misoprostol (range $150.12 to $272.73) (Table
6.4(2)). The cost per induction with misoprostol for nulliparous women with an initial
Bishop’s score of 4-6 was $5,046.14, compared with $5,156.25 per induction with
vaginal PGE2 gel, a difference of $110.11 in favour of misoprostol (range $55.32 to
$176.31) (Table 6.4(3)). For multiparous women, the cost per induction with
misoprostol was $4,574.67 where the initial Bishop’s score was 0-3, and $4,487.82
where the initial Bishop’s score was 4-6 (Tables 6.4(4) and 6.4(5)). This equates to a
difference in cost of $186.98 (range $68.78 in favour of vaginal PGE2 to $300.66 in
favour of misoprostol), and $14.42 (range $49.37 in favour of vaginal PGE2 to $31.40
in favour of misoprostol) respectively, when compared with induction with vaginal
PGE2 gel.
124
Table 6.4(1) Costs for all women
Outcome measured Misoprostol
Group N=365
Cost Australian $
PGE2 Group N=376
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
13.7 65 207.25 11.5 56 384.96
Length of labour^ (1:1.25 midwifery care) 7.5 89 242.50 6.9 84 577.44 Doses of trial medication 1 668 583.80 342 x 2mg
239 x 1mg 17 660.88 9 600.63
Further doses known 2mg PGE2 gel 70 3 614.80 47 2 427.08 Vaginal birth 282 1 120 620.00 276 1 096 777.00 Caesarean birth 83 527 047.51 100 634 997.00 Total Cost 1 806 315.80 1 902 424.90 Total Cost per Woman 4 948.81 5 059.64 110.83 Cost per 100 Women induced 494 881.05 505 964.09
Outcome measured – Lower Threshold Misoprostol
Group N=365
Cost Australian $
PGE2 Group N=376
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
5.2 24 749.92 2.9 35 547.04
Length of labour^ (1:1.25 midwifery care) 3.4 40 456.60 3.4 16 670.34 Doses of trial medication 1 668 583.80 342 x 2mg
239 x 1mg 17 660.88 9 600.63
Further doses known 2mg PGE2 gel 42 2 168.88 28 1 445.92 Vaginal birth 297 1 180 227.50 294 1 168 306.00 Caesarean birth 68 431 797.96 82 520 697.54 Total Cost 1 679 984.60 1 736 587.60 Total Cost per Woman 4 602.70 4 618.58 15.88 Cost per 100 Women induced 460 269.76 461 858.42
Outcome measured – Upper Threshold Misoprostol
Group N=365
Cost Australian $
PGE2 Group N=376
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
22.2 105 663.12 19.6 96 099.58
Length of labour^ (1:1.25 midwifery care) 11.6 138 028.40 10.9 133 607.84 Doses of trial medication 1 668 583.80 342 x 2mg
239 x 1mg 17 660.88 9 600.63
Further doses known 2mg PGE2 gel 109 5 628.76 73 3 769.72 Vaginal birth 262 1 041 143.40 252 1 001 405.10 Caesarean birth 103 654 046.91 124 787 396.28 Total Cost 1 945 094.30 2 049 540.00 Total Cost per Woman 5 329.03 5 450.90 121.87 Cost per 100 Women induced 532 902.57 545 090.43
*Median interval in hours
^Mean interval in hours
125
Table 6.4(2) Costs nulliparous women with Bishop’s score 0-3
Outcome measured Misoprostol
Group N=143
Cost Australian $
PGE2 Group N=126
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
16.2 30 208.46 14.1 23 166.86
Length of labour^ (1:1.25 midwifery care) 9.6 44 753.28 8.7 35 736.12 Doses of trial medication 755 264.25 208 10 741.12 Further doses known 2mg PGE2 gel 48 2 478.72 19 981.16 Vaginal birth 94 373 540.02 73 290 089.59 Caesarean birth 49 311 148.53 53 336 548.41 Total Cost 762 393.26 697 263.26 Total Cost per Woman 5 331.42 5 533.84 202.42 Cost per 100 women induced 533 142.13 553 383.53
Outcome measured – Lower Threshold Misoprostol
Group N=143
Cost Australian $
PGE2 Group N=126
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
9.1 16 968.95 5.3 8 708.11
Length of labour^ (1:1.25 midwifery care) 5.4 25 173.72 4.6 18 894.96 Doses of trial medication 755 264.25 208 10 741.12 Further doses known 2mg PGE2 gel 8 413.12 3 154.92 Vaginal birth 104 413 278.32 84 333 801.72 Caesarean birth 39 247 648.83 42 266 698.74 Total Cost 703 747.19 638 999.57 Total Cost per Woman 4 921.31 5 071.43 150.12 Cost per 100 women induced 492 130.90 507 142.51
Outcome measured – Upper Threshold Misoprostol
Group N=143
Cost Australian $
PGE2 Group N=126
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
23.9 44 566.81 22.9 37 625.62
Length of labour^ (1:1.25 midwifery care) 13.2 61 535.76 12.8 52 577.28 Doses of trial medication 755 264.25 208 10 741.12 Further doses known 2mg PGE2 gel 113 5 835.32 45 2 323.80 Vaginal birth 79 313 932.57 57 226 508.31 Caesarean birth 64 406 398.08 69 438 147.93 Total Cost 832 532.79 767 924.06 Total Cost per Woman 5 821.91 6 094.64 272.73 Cost per 100 women induced 582 190.76 609 463.53
*Median interval (in hours)
^Mean interval (in hours)
126
Table 6.4(3) Costs for nulliparous women with Bishop’s score 4-6
Outcome measured Misoprostol
Group N=70
Cost Australian $
PGE2 Group N=95
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
13.0 11 866.40 10.3 12 759.64
Length of labour^ (1:1.25 midwifery care) 8.7 19 853.40 8.3 25 705.10 Doses of trial medication 305 106.75 134 6 919.76 Further doses known 2mg PGE2 gel 9 464.76 8 413.12 Vaginal birth 52 206 639.16 67 266 246.61 Caesarean birth 18 114 299.46 28 177 799.16 Total Cost 353 229.93 489 843.39 Total Cost per Woman 5 046.14 5 156.25 110.11 Cost per 100 women induced 504 614.18 515 624.62
Outcome measured – Lower Threshold Misoprostol
Group N=70
Cost Australian $
PGE2 Group N=95
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
7.0 6 389.60 3.5 4 335.80
Length of labour^ (1:1.25 midwifery care) 4.5 10 269.00 4.1 12 697.70 Doses of trial medication 305 106.75 134 6 919.76 Further doses known 2mg PGE2 gel 1 51.64 1 51.64 Vaginal birth 58 230 482.14 77 305 984.91 Caesarean birth 12 76 199.64 18 114 299.46 Total Cost 323 498.77 444 289.27 Total Cost per Woman 4 621.41 4 676.73 55.32 Cost per 100 women induced 462 141.10 467 672.91
Outcome measured – Upper Threshold Misoprostol
Group N=70
Cost Australian $
PGE2 Group N=95
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
19.0 17 343.20 17.1 21 183.48
Length of labour^ (1:1.25 midwifery care) 12.9 29 437.80 12.5 38 712.50 Doses of trial medication 305 106.75 134 6 919.76 Further doses known 2mg PGE2 gel 29 1 497.56 26 1 342.64 Vaginal birth 42 166 900.86 51 202 665.33 Caesarean birth 28 177 799.16 44 279 398.68 Total Cost 393 085.33 550 222.39 Total Cost per Woman 5 615.50 5 791.81 176.31 Cost per 100 women induced 561 550.47 579 181.46
* Median interval (in hours)
^Mean interval (in hours)
127
Table 6.4(4) Costs for multiparous women with Bishop’s score 0-3
Outcome measured Misoprostol
Group N=103
Cost Australian $
PGE2 Group N=88
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
11.1 14 908.63 12.5 14 344.00
Length of labour^ (1:1 midwifery care) 5.3 17 796.34 5.3 15 204.64 Doses of trial medication 433 151.55 139 5 583.63 Further doses known 2mg PGE2 gel 10 516.40 18 929.52 Vaginal birth 91 361 618.53 74 294 063.42 Caesarean birth 12 76 199.64 14 88 899.58 Total Cost 471 191.09 419 024.79 Total Cost per Woman 4 574.67 4 761.65 186.98 Cost per 100 women induced 457 467.07 476 164.53
Outcome measured – Lower Threshold Misoprostol
Group N=103
Cost Australian $
PGE2 Group N=88
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
3.6 12 088.08 4.2 4 819.58
Length of labour^ (1:1 midwifery care) 2.2 7 387.16 1.5 4 303.20 Doses of trial medication 433 151.55 139 5 583.63 Further doses known 2mg PGE2 gel 8 413.12 14 722.96 Vaginal birth 95 377 513.85 83 329 827.89 Caesarean birth 8 50 799.76 5 31 749.85 Total Cost 448 353.52 377 007.11 Total Cost per Woman 4 352.95 4 284.17 -68.78 Cost per 100 women induced 435 294.67 428 417.17
Outcome measured – Upper Threshold Misoprostol
Group N=103
Cost Australian $
PGE2 Group N=88
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
18.6 24 982.03 21.4 24 556.93
Length of labour^ (1:1 midwifery care) 8.4 28 205.52 8.5 24 384.80 Doses of trial medication 433 151.55 139 5 583.63 Further doses known 2mg PGE2 gel 15 774.60 27 1 394.28 Vaginal birth 82 325 854.06 63 250 351.29 Caesarean birth 21 133 349.37 25 158 749.25 Total Cost 513 317.13 465 020.18 Total Cost per Woman 4 983.66 5 284.32 300.66 Cost per 100 women induced 498 366.14 528 432.02
*Median interval (in hours)
^Mean interval (in hours)
128
Table 6.4(5) Costs for multiparous women with Bishop’s score 4-6
Outcome measured Misoprostol
Group N=49
Cost Australian $
PGE2 Group N=67
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
8.7 5 558.95 9.8 8 562.06
Length of labour^ (1:1 midwifery care) 6.2 9 903.88 5.0 10 921.00 Doses of trial medication 180 63.00 98 3 936.66 Further doses known 2mg PGE2 gel 3 154.92 2 103.28 Vaginal birth 45 178 822.35 62 246 377.46 Caesarean birth 4 25 399.88 5 31 749.85 Total Cost 219 902.98 301 650.31 Total Cost per Woman 4 487.82 4 502.24 14.42 Cost per 100 women induced 448 781.59 450 224.34
Outcome measured – Lower Threshold Misoprostol
Group N=49
Cost Australian $
PGE2 Group N=67
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
2.1 1 341.82 4.6 4 018.93
Length of labour^ (1:1 midwifery care) 2.9 4 632.46 1.5 3 276.30 Doses of trial medication 180 63.00 98 3 936.66 Further doses known 2mg PGE2 gel 0 0.00 0 0.00 Vaginal birth 48 190 743.84 66 262 272.78 Caesarean birth 1 6 349.97 1 6 349.97 Total Cost 203 131.09 279 854.64 Total Cost per Woman 4 145.53 4 176.93 31.40 Cost per 100 women induced 414 553.24 417 693.49
Outcome measured – Upper Threshold Misoprostol
Group N=49
Cost Australian $
PGE2 Group N=67
Cost Australian $
Induction to birth interval* - Length of Labour (1:2 midwifery care)
15.3 9 776.09 15.0 13 105.20
Length of labour^ (1:1 midwifery care) 9.5 15 175.30 8.5 18 565.70 Doses of trial medication 180 63.00 98 3 936.66 Further doses known 2mg PGE2 gel 32 1 652.48 22 1 136.08 Vaginal birth 34 135 110.22 48 190 743.84 Caesarean birth 15 95 249.55 19 120 649.43 Total Cost 257 026.64 348 136.91 Total Cost per Woman 5 245.44 5 196.07 -49.37 Cost per 100 women induced 524 544.16 519 607.32
*Median interval (in hours)
^Mean interval (in hours)
129
The drug costs per woman induced with misoprostol (including the need for further
known doses of vaginal PGE2 gel) were $11.50 compared with $72.50 per woman
induced with vaginal PGE2 gel, a difference of $61.00 per women in favour of
misoprostol. The drug costs for women induced with misoprostol ranged from $19.18
per nulliparous woman with an initial Bishop’s score of 0-3, to $4.48 per multiparous
woman with an initial Bishop’s score of 4-6. In contrast, the drug costs per woman
induced with vaginal PGE2 gel ranged from $93.03 per nulliparous woman with an
initial Bishop’s score of 0-3, to $60.30 per multiparous woman with an initial Bishop’s
score of 4-6 (Figure 6.4(1)). The difference in drug costs per woman induced ranged
from $73.85 per nulliparous woman with an initial Bishop’s score of 0-3, to $55.85 per
multiparous woman with an initial Bishop’s score of 4-6, both in favour of misoprostol.
Figure 6.4(1) Drug Costs per Woman Induced
0102030405060708090
100
Allwomen
Para0,BS0-3
Para0,BS4-6
Para1+,BS0-3
Para 1+,BS4-6
Cos
t (A
us $
)
MisoprostolVaginal PGE2
130
6.5 DISCUSSION
Interest in the use of misoprostol as an induction of labour agent has rapidly increased,
related in part to its lower cost when compared with other prostaglandin preparations
used in obstetric practice. There is an obvious cost differential between oral misoprostol
and vaginal PGE2 gel. A change to the use of misoprostol as the primary induction
agent for women at term would result in a potential saving of around $11,000.00 for
every 100 women induced to the Women’s and Children’s Hospital, even accounting
for slightly reduced clinical efficacy, particularly in nulliparous women with an initial
Bishop’s score of 0-3. However, even in this group of women, where there may be need
for further doses of vaginal PGE2 gel, the potential savings in drug costs alone increase
to $7,385.00 per 100 women induced with misoprostol.
In addition to this difference in drug costs, there are other costs associated with
induction of labour. Any difference in efficacy between misoprostol and vaginal PGE2
gel needs to be balanced against a potential increase in adverse events for both the
woman and infant. Several authors have attempted to elucidate these differences further
(Sanchez-Ramos 1993; Wing 1995a; Kramer 1997; Sanchez-Ramos 1997), but none
have been readily applicable to an Australian setting.
The results of this cost comparison indicate a modest saving not only in drug related
costs, but also hospital related costs of the order of $11,000 for every 100 women
induced with misoprostol. This difference is greatest for the induction of nulliparous
women with an initial Bishop’s score of 0-3, where the cost differential is in excess of
$20,000 for every 100 women induced with misoprostol. The difference in costs reflects
not only a reduction in drug costs, but also a 15% reduction in caesarean section in this
group of women. From a perspective considering cost alone, this modest saving offsets
any reduction in efficacy as indicated by a need for further doses of known vaginal
PGE2 gel, oxytocin infusion during labour, and increased midwifery care costs as
indicated by a longer induction to birth interval. However, the cost of midwifery care in
this analysis utilised hourly rates for a junior midwife and did not take into account
penalty salary rates, or the use of agency staff, who are often “bought-in” during busy
periods. In these situations, salary costs would be greater than those considered in this
comparison.
131
In an obstetric unit with approximately 1,400 inductions per year, as is the case for the
Women’s and Children’s Hospital, changing to the use of misoprostol has the potential
to save in excess of $154,000 annually.
While hospital administrators and health economists could make an argument
supporting the use of misoprostol as an induction agent, it is unlikely that this will
propel manufacturers towards seeking appropriate product licensing for the use of
misoprostol in pregnancy. There is economic advantage to health service providers in
the use of misoprostol for induction of labour, although its low production cost does not
translate into financial incentives for the manufacturers. Efforts should be directed to
ensure that a low dose (20mcg) formulation of misoprostol is available, is easy to
administer orally for both women and their caregivers, and retains its current low cost to
enable its widespread use, particularly in under-resourced countries.
6.6 CONCLUSION
There would be a cost saving to the Women’s and Children’s Hospital associated with a
change from vaginal PGE2 gel to oral misoprostol as the primary induction of labour
agent of the order of $154,000 annually. The use of misoprostol as an induction agent
has potential for reduction in both drug and hospital care costs for developed nations, in
addition to providing an economical method of induction of labour in under resourced
countries.
132
7. MISOPROSTOL FOR INDUCTION OF LABOUR AT TERM – AN UPDATED META-ANALYSIS
7.1 INTRODUCTION
Systematic reviews collate information from primary RCTs that address the same (or
similar) research question (Greenhalgh 1997b; Greenhalgh 1997c), allowing
information to be assimilated and increasing the statistical power and available sample
size (Sacks 1987; Mulrow 1994; Thacker 1998). It allows an assessment to be made of
how applicable the findings are to the general population, in addition to the consistency
of results across trials, both in direction and magnitude of effect (Sacks 1987; Mulrow
1994; Thacker 1998).
7.2 STUDY AIMS AND HYPOTHESES
The aims of this study are to incorporate the information generated from the randomised
double blind placebo controlled trial comparing oral misoprostol with vaginal PGE2 gel
into the currently available published literature, and to update the meta-analysis
described in Chapter 2.
7.3 METHODS
The methods of the systematic review have been described previously in Chapter 2. The
current randomised controlled trial conforms with the stated inclusion criteria and will
be included in an updated meta-analysis.
133
7.4 RESULTS
7.4(1) Description of Studies
The characteristics of the identified randomised controlled trials are described in
Chapter 2. The characteristics of the current randomised trial are described in detail in
Chapter 3 and summarised below in Table 7.4(1).
Table 7.4(1) Summary characteristics of the current randomised trial
Trial Identification Trial Characteristics
Dodd 2005 Methods: Trial conducted at the Women’s and Children’s Hospital, Lyell McEwin Health Service (South Australia) and Hervey Bay Hospital (Queensland) between April 2001 and December 2004 Participants: Women with a singleton pregnancy in cephalic presentation at 366 weeks gestation with an indication for induction of labour; exclusion criteria include active labour, Bishop’s score >7, contraindication to vaginal birth, pervious uterine surgery (including caesarean section), maternal history of asthma, glaucoma, or heart disease, ruptured membranes, parity >5, suspected cephalopelvic disproportion, abnormal fetal lie, breech presentation, non-reassuring fetal heart rate tracing, multiple pregnancy, intrauterine infection, vasa praevia or placenta praevia, active genital herpes, maternal illness precluding induction, maternal hepatic or renal failure Interventions: 20mcg oral misoprostol solution at 2 hourly intervals (maximum 6 doses in 12 hours) and vaginal placebo gel (at 6 hourly intervals to a maximum of 2 doses in 12 hours) vs vaginal PGE2 gel at 6 hourly intervals (maximum 2 doses in 12 hours) and oral placebo (vitamin B6 solution at 2 hourly intervals to a maximum of 6 doses in 12 hours) Sample size: 741 women Primary Outcomes: Vaginal birth not achieved in 24 hours, uterine hyperstimulation with fetal heart rate changes, caesarean section (all and for fetal distress) Randomisation: computer generated sequence using variable blocks with stratification for maternal parity (A) Allocation Concealment: Sequentially numbered identical appearing treatment packs (A) Blinding: All women, caregivers and outcome assessors blinded to allocated treatment
7.4(2) Meta-analysis
There were no differences in the number of women administered oral misoprostol
achieving vaginal birth within 24 hours of the induction commencing when compared
with women administered vaginal PGE2 gel (4 trials, 1781 participants, RR 1.11, 95%
CI 0.99-1.24), with the magnitude and direction of effect similar between trials (Table
134
7.4(2)(i), Figure 7.4(2)(i)). There were no differences in the occurrence of uterine
hyperstimulation syndrome with associated fetal heart rate changes (6 trials, 2128
participants, RR 0.80, 95% CI 0.52-1.23) (Figure 7.4(2)(ii)) or caesarean section (6
trials, 2158 participants, RR 0.91, 95% CI 0.77-1.06) (Figure 7.4(2)(iii)) between
women administered oral misoprostol and women administered vaginal PGE2. There
were no reports of serious neonatal (2 trial, 1008 participants, RR not estimable) or
maternal morbidity (3 trials, 1073 participants, RR not estimable) in those trials
reporting these outcomes.
Women administered oral misoprostol were more likely to have no evidence of cervical
change after 12 or 24 hours (2 trials, 930 participants, RR 1.41, 95% CI 1.01-1.96)
(Figure 7.4(2)(iv)), and to require an oxytocin infusion during labour (3 trials, 999
participants, RR 1.22, 95% CI 1.09-1.38) when compared with women administered
vaginal PGE2 (Table 7.4(2)(ii)) (Figure 7.4(2)(v)).
For maternal and neonatal complications, there were no differences identified between
oral misoprostol and vaginal PGE2 (Table 7.4(2)(iii) and Table 7.4(2)(iv)).
A single trial only reported maternal satisfaction with care, as described in Chapter 4.
Table 7.4(2)(i) Meta-analysis of Primary Outcomes
Outcome No.
Trials
No.
Participants
Relative Risk 95% CI
Vaginal birth not achieved in 24 hours 4 1781 1.11 0.99-1.24
Hyperstimulation with FHR changes 6 2128 0.80 0.52-1.23
Caesarean section (all) 6 2158 0.91 0.77-1.06
Serious neonatal morbidity 2 1008 Not estimable
Serious maternal morbidity 3 1703 Not estimable
135
Figure 7.4(2)(i) Vaginal birth not achieved in 24 hours
Figure 7.4(2)(ii) Uterine hyperstimulation with associated fetal heart
rate changes
igure 7.4(2)(iii) Caesarean sectionF
136
Table 7.4(2)(ii) Meta-analysis of Secondary Outcomes – Evidence of
Effect
Outcome No.
Trials
No.
Participants
Relative Risk 95% CI
Cervix unchanged 12-24 hours 2 930 1.41 1.01- 1.96
Need for oxytocin augmentation 3 999 1.22 1.09- 1.38
Induction – birth interval* 4 1157 -1.38 -2.60- -0.15
Figure 7.4(2)(iv) Cervix unchanged after 12/24 hours
Figure 7.4(2)(v) Need for oxytocin infusion
137
Table 7.4(2)(iii) Meta-analysis of Secondary Outcomes – Maternal
Complications
Outcome No.
Trials
No.
Participants
Relative Risk 95% CI
Hyperstimulation no FHR changes 3 1603 0.77 0.51-1.16
Uterine rupture 3 1632 Not estimable
Epidural analgesia 3 999 1.05 0.96-1.14
Instrumental vaginal birth 4 1833 0.89 0.74-1.07
Maternal side effects – any 3 1632 1.00 0.86-1.17
Maternal side effects – nausea 3 999 1.04 0.70-1.56
Maternal side effects – vomiting 3 1632 1.11 0.79-1.54
Maternal side effects – diarrhoea 2 200 0.33 0.01-8.09
Post partum haemorrhage 3 1633 0.90 0.74-1.11
Maternal Death 2 1433 Not estimable
Table 7.4(2)(iv) Meta-analysis of Secondary Outcomes – Neonatal
Complications
Outcome No.
Trials
No.
Participants
Relative Risk 95% CI
Meconium Stained Liquor 4 1199 1.11 0.85- 1.46
Apgar Score <7 at 5 minutes 4 1690 0.64 0.64- 1.24
Admission to NICU 4 1832 0.87 0.56- 1.37
Perinatal Death 3 1699 1.00 0.06-15.97
138
7.5 DISCUSSION
The use of oral misoprostol was not associated with an increase in the chance of a
woman not giving birth vaginally within 24 hours, caesarean section, or uterine
hyperstimulation with associated fetal heart rate changes. Women who received oral
misoprostol were more likely to have no evidence of cervical change after 12 or 24
hours, and to require oxytocin infusion during labour when compared with vaginal
PGE2 gel, a consistent effect across studies.
This updated meta-analysis includes 6 randomised controlled trials comparing oral
misoprostol with vaginal PGE2 gel, and involves 2,158 women and their infants. While
two of the included trials were double blind, 53.3% of the participants and their
caregivers were aware of the treatment allocated. However, the findings of the largest
randomised controlled trial to date are consistent in direction and magnitude of
treatment effect with the other reported studies, including the two randomised trials
comparing low dose oral misoprostol solution with vaginal PGE2 gel (Hofmeyr 2001;
Dallenbach 2003).
It was not possible to explore the effect of Bishop’s score at the start of induction
(Bishop’s score 0-3 versus Bishop’s score 4-6), or the effect of maternal parity
(nulliparous versus multiparous) to determine the existence of any differential treatment
effect, as these parameters were reported in one study only (Chapter 3).
There was a consistent trend towards fewer caesarean sections in the oral misoprostol
group, particularly in the studies utilising a low dose misoprostol solution, of the order
of 10 to 15%. To reliably be able to detect a change of this magnitude would require a
combined sample size of the order of 4,000 women, short of the achieved sample in this
meta-analysis. The occurrence of uterine hyperstimulation with associated fetal heart
rate changes was not different between women receiving oral misoprostol and women
receiving vaginal PGE2 gel. However, to be able to detect the 20% difference suggested
from the meta-analysis, from 4.1% in the vaginal PGE2 group to 3.3% in the oral
misoprostol group, would require a sample size of almost 18,000 women.
139
The extent of rare but potentially serious adverse complications such as uterine rupture,
maternal or perinatal death, and neonatal acidaemia remain uncertain, as the present
sample size of the meta-analysis is underpowered to detect all but extraordinarily large
differences. While it is unrealistic to expect randomised trials to be conducted that are
able to recruit tens of thousands of women and their infant’s, regular audit of clinical
practice and reporting of such adverse outcomes should be an essential requirement of
clinicians and institutions adopting the use of misoprostol in the induction of labour.
The outcome vaginal birth not achieved in 24 hours as defined in the Cochrane generic
protocol (Hofmeyr 2005a) comprises both women who birth vaginally beyond 24 hours
and all women who birth by caesarean section. These two components reflect different
processes whereby misoprostol may generate adverse health outcomes. If vaginal birth
is achieved beyond 24 hours, it may reflect an inappropriately low dose of misoprostol.
The alternative process contributing to adverse health outcomes relates to uterine
hyperstimulation with fetal heart rate changes and subsequent birth by caesarean section
for non-reassuring fetal heart rate trace. For completeness and to ensure clarity of
information, future trials should report both components of this outcome.
7.6 CONCLUSION
Oral misoprostol is as effective as vaginal PGE2 gel for the induction of labour at or
near term, with no increase in the chance of a woman not birthing vaginally within 24
hours, caesarean section, or uterine hyperstimulation with associated fetal heart rate
changes. Oral misoprostol was associated with an increased need for further doses of
vaginal PGE2 gel and oxytocin infusion, but these differences in the process of
induction did not lead to poorer health outcomes for women or infants.
140
8. OVERALL CONCLUSIONS
8.1 ORAL MISOPROSTOL VERSUS VAGINAL PROSTAGLANDIN E2 GEL FOR INDUCTION OF LABOUR
Oral misoprostol was not associated with differences in the number of women who
achieve vaginal birth in 24 hours, uterine hyperstimulation with fetal heart rate changes,
or caesarean section, compared with vaginal PGE2 gel.
Oral misoprostol was associated with an increased need for further doses of vaginal
PGE2 gel and oxytocin infusion, but a significant reduction in uterine hyperstimulation
without fetal heart rate changes. Differences in the process of induction did not lead to
poorer health outcomes for women or infants.
An initial Bishop’s score of 0-3 at the start of induction and nulliparity are both
independently associated with greater difficulty in inducing labour, particularly when
using misoprostol. These differences in the process of initiating labour are most
pronounced among nulliparous women with an initial Bishop’s score of 0-3. However,
these differences are not associated with an increase in the risk of adverse health
outcomes for the woman or her infant.
For nulliparous women with a Bishop’s score of 0-3, a dose of 20mcg oral
misoprostol is less effective in achieving vaginal birth within 24 hours when
compared with vaginal PGE2 gel.
Oral misoprostol for the induction of labour is not associated with an increase in
the risk of adverse health outcomes for the woman or her infant.
141
For multiparous women, 20mcg of oral misoprostol is as effective as vaginal PGE2 gel
in the process of initiating labour, with no increased risk of adverse health outcomes for
the woman or her infant.
8.2 WOMEN’S PREFERENCES FOR CARE
Overall, women expressed a high degree of satisfaction with their induction, labour, and
birth, and a strong preference for an oral induction of labour agent. Women in the oral
misoprostol group were more likely to indicate that they “liked everything” associated
with their induction and birth experience.
While women in the misoprostol group were more likely to remain undelivered after 24
hours, this did not impact negatively on their birth experience. Of women who were
undelivered after 24 hours, more in the misoprostol group indicated that they “liked
everything” associated with their induction and birth.
For multiparous women, 20mcg of oral misoprostol is as effective as
vaginal PGE2 gel.
Women have a strong preference for an oral induction of labour agent.
Women administered misoprostol were more likely to be satisfied with all aspects
of their labour and birth experience.
8.3 TIME OF ADMISSION FOR INDUCTION OF LABOUR
Admission in the morning for induction to start was associated with no differences in
the chance of a woman remaining undelivered after 24 hours when compared with
evening admission. However, admission in the morning was associated with less need
for oxytocin infusion, a shorter induction to birth interval, and less need for
instrumental vaginal birth.
142
Overall, women expressed a high degree of satisfaction, although women admitted for
induction in the evening were more likely to dislike interruptions to their sleep.
8L
A
o
H
$
a
a
Women should be offered admission in the morning to start induction of labour
as it is associated with less need for intervention, a shorter induction to birth
interval, and less disruption to sleep.
.4 COSTS ASSOCIATED WITH INDUCTION OF ABOUR
change from the use of vaginal PGE2 gel to oral misoprostol as the primary induction
f labour agent would be associated with a saving to the Women’s and Children’s
ospital, where approximately 1,400 women have their labour induced per annum, of
154,000 annually. This modest saving offsets any reduction in efficacy as indicated by
need for further doses of known vaginal PGE2 gel, oxytocin infusion during labour,
nd increased midwifery care costs as indicated by a longer induction to birth interval.
p
w
Use of oral misoprostol as the primary induction of labour agent has the
otential to save institutions such as the Women’s and Children’s Hospital,
here 1,400 women have their labour induced each year, $154,000 annually.
143
8.5 IMPLICATIONS FOR CLINICAL PRACTICE
The use of oral misoprostol for induction of labour is not associated with differences in
a woman’s chance of not achieving vaginal birth within 24 hours, caesarean section,
uterine hyperstimulation with associated fetal heart rate changes, or adverse health
outcomes for the woman or her infant when compared with vaginal PGE2 gel.
The women’s own preferences were clear. Women expressed a strong preference for an
oral induction of labour agent, with women administered misoprostol more likely to
“like everything” associated with their labour and birth experience. Furthermore,
women who remain undelivered after 24 hours and were administered misoprostol were
more likely to indicate that that they “like(d) everything” associated with their birth
experience. There was a modest cost saving in the use of misoprostol.
Potential Positive Effects in the use of Misoprostol compared with Vaginal PGE2
gel in the Induction of Labour
• No increase in the risk of not achieving vaginal birth within 24 hours
• No increase in the risk of uterine hyperstimulation with associated fetal
heart rate changes
• No increase in the risk of caesarean section
• No difference in the chance of labour and birth complications
• No difference in the chance of neonatal complications
• No difference in maternal side effects or complications
• Women express a strong preference for an oral induction of labour agent
• Women “like everything” associated with their labour & birth experience
• A cost saving to the institution
144
Use of oral misoprostol for induction of labour is associated with an increased chance of
there being no cervical change after 24 hours, of needing further doses of vaginal gel, of
needing an oxytocin infusion, of needing any analgesia during labour, and a longer
induction to birth interval when compared with vaginal PGE2 gel.
While these relative differences that relate to the birth process are statistically
significant, the absolute differences between the two treatment groups are of similar
magnitude, and the clinical significance of the negative differences observed is offset by
potential benefits.
Potential Negative Effects in the use of Misoprostol compared with Vaginal PGE2
gel in the Induction of Labour
• Increased chance of no cervical change after 24 hours
(15% misoprostol versus 10% PGE2)
• Increased chance of needing further vaginal PGE2 gel
(19% misoprostol versus 13% PGE2)
• Increased chance of requiring oxytocin infusion during labour
(56% misoprostol versus 48% PGE2)
• Increased chance of needing any analgesia during labour
(96% misoprostol versus 92% PGE2)
• Longer induction to birth interval
(21 hours misoprostol versus 18 hours PGE2)
145
Misoprostol should be available for use in the induction of labour of women at
term. Misoprostol is not associated with an increase in the chance of remaining
undelivered vaginally within 24 hours, caesarean section, uterine hyperstimulation
with fetal heart rate changes, or adverse health outcomes for women or their
infants. Women express a preference for an oral induction agent that is associated
with a more positive birth experience, and its use is associated with modest cost
savings to the institution.
Women should be offered admission in the morning to start induction of labour, as
it is associated with a reduction in intervention, a shorter induction to birth
interval, and less disruption to sleep. This is particularly the case for nulliparous
women.
8.6 IMPLICATIONS FOR RESEARCH
Further information is required about the lowest effective dose of misoprostol in
nulliparous women, and in particular those women with an initial Bishop’s score of 0-3.
However, any increase in dose, while improving clinical efficacy must be balanced
against a potential increase in side effects and adverse complications for the woman and
her infant. While the use of titrated doses or oral misoprostol has been addressed in the
trials by Hofmeyr (2001) and Dallenbach (2003), it would be interesting to explore any
variations in the evidence of effect of misoprostol in nulliparous women with an initial
Bishop’s score of 0-3 through subgroup analysis of their primary trial data.
The outcome vaginal birth not achieved in 24 hours as defined in the Cochrane generic
protocol (Hofmeyr 2005a) comprises both women who birth vaginally beyond 24 hours
and all women who birth by caesarean section. For completeness and to ensure clarity
of information, future trials should report both components of this outcome.
Further studies are required to address the optimal timing of admission for induction of
labour, and the suggestion of diurnal variations in clinical practice identified in the
current trial. Any benefits of morning admission for the woman in terms of reduced
intervention and a shorter induction to birth interval must be balanced against a
146
recognised risk of adverse neonatal outcome associated with birth during the evening
and night. However, to assess the risk of rare adverse neonatal health outcomes
adequately, it would be necessary to recruit tens of thousands of women and their
infants in prospective randomised trials.
Efforts should be directed towards ensuring that pharmaceutical companies manufacture
a low dose (20mcg) formulation of misoprostol that is easy to administer orally for both
women and their caregivers, and retains its current low cost to enable its widespread
use, particularly in under-resourced countries.
147
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