35/39 trial
Induction of labour versus expectant management for nulliparous women over 35 years of age
Final Version number 9, 30.09.2013
MAIN SPONSOR: Nottingham University Hospitals NHS Trust
FUNDERS: NIHR Research for Patient Benefit Programme
STUDY COORDINATION CENTRE: Nottingham University
Hospitals NHS Trust
NRES reference: 12/EM/0003
ISRCTN11517275
Protocol authorised by:
Name & Role / Date / SignatureProf J Thornton – Chief Investigator / 28.03.2012
35/39 study Page 2 of 14 Version Final 9 30.09.2013
Study Management Group
Chief Investigator: Professor James Thornton
Co-investigators: Dr Kate Walker, Mr George Bugg, Miss Marion Macpherson, Miss Carol McCormick, Mr Chris Wildsmith, and Professor Gordon Smith
Statistician: Dr Samir Mehta, University of Nottingham
Study Management: Professor James Thornton, Dr Kate Walker, Mr George Bugg, Miss Marion Macpherson, Miss Carol McCormick, Mr Chris Wildsmith, and Professor Gordon Smith
Study Coordination Centre
For general queries, supply of study documentation, and collection of data, please contact:
Study Coordinator: Dr Kate Walker, Clinical Research Fellow in Obstetrics and Gynaecology
Address: Maternity Unit, Nottingham City Hospital
Direct Tel: 0115 823 1893
Bleep number: 7086 (via hospital switchboard 0115 969 1169)
E-mail:
Fax: 01158231508
Website: http://www.35-39trial.org/
Clinical Queries
Clinical queries should be directed to Dr Kate Walker who will direct the query to the appropriate person
Sponsor
Nottingham University Hospitals NHS Trust is the main research sponsor for this study. For further information regarding the sponsorship conditions, please contact the Research Governance Manager at:
Research & Innovation
Nottingham Integrated Clinical Research Centre,
C floor, South Block,
Queens Medical Centre Campus,
Nottingham University Hospitals NHS Trust,
Nottingham,
NG7 2UH
Telephone: 0115 9249924
Funder
National Institute for Health Research – Research for Patient Benefit Programme
This protocol describes the 35/39 study and provides information about procedures for entering participants. Every care was taken in its drafting, but corrections or amendments may be necessary. These will be circulated to investigators in the study. Problems relating to this study should be referred, in the first instance, to the Chief Investigator.
This study will adhere to the principles outlined in the NHS Research Governance Framework for Health and Social Care (2nd edition). It will be conducted in compliance with the protocol, the Data Protection Act and other regulatory requirements as appropriate.
Table of Contents
1. INTRODUCTION 7
1.1 BACKGROUND 7
2. STUDY OBJECTIVES 8
3. STUDY DESIGN 8
3.1 Study outcome measures 9
4. Participant Entry 11
4.1 Pre-registration evaluations 11
4.2 Inclusion Criteria 11
4.3 EXCLUSION CRITERIA 11
4.4 WithdrawAl criteria 11
5. adverse events 11
5.1 Definitions 11
5.3 Reporting Procedures 12
6. ASSESSMENT AND FOLLOW-UP 12
7. STATISTICs and data analysis 13
8. regulatory issues 13
8.1 Ethics approval 13
8.2 Consent 14
8.3 Confidentiality 14
8.4 Indemnity 14
8.5 Sponsor 14
8.6 Funding 14
8.7 Audits 14
9. Study Management 14
10. Publication Policy 14
11. References 14
Glossary of Abbreviations
BP / Blood pressureCS / Caesarean Section
EDD / Expected date of delivery
IVF / In vitro fertilisation
RCT / Randomised Controlled Trial
Keywords
Induction of labour; advanced maternal age; perinatal outcome; caesarean delivery
Study Summary
TITLE / Induction of labour versus expectant management for nulliparous women over 35 years of ageDESIGN / A multi-centre prospective randomised controlled trial
AIMS / The purpose of this trial is to establish what effect a policy of induction of labour at 39 weeks for nulliparous women of advanced maternal age has on the rate of Caesarean section deliveries. The secondary aim is to act as a pilot study for a trial to answer the question, does induction of labour in this group of women improve perinatal outcomes.
POPULATION / Nulliparous women with a singleton live fetus who will be over 35 years of age at their expected date of delivery
ELIGIBILITY / · A cephalic presentation
· Gestational age between 360/7 and 396/7
· No medical contra-indication to induction of labour
· No medical contra-indication to pregnancy being allowed to proceed to term plus 10 days
· Willingness to participate in the trial
· Written informed consent
OUTCOME MEASURES / Primary end point: Caesarean delivery
Secondary end points: Operative vaginal delivery, perinatal mortality, neonatal mortality, serious neonatal morbidity, and maternal expectation/experience.
duration / 24 months
1. INTRODUCTION
1.1 BACKGROUND
The average age at childbirth in the UK is increasing, and more women are giving birth over the age of 35 years (CEMACH, 2007). In 1996, 12% of live births were to women over the age of 35 years, by 2006 that figure had risen to 20%. The Office of National Statistics estimate that in 2006, 5.6% of live births were to nulliparous women over the age of 35 years. In Scotland the figure is 9% (Smith et al, 2008).
Women over 35 years are at higher risk of antepartum and intrapartum stillbirths and neonatal deaths (Perinatal Mortality 2008), of hypertensive disorders, gestational diabetes, placenta praevia and placental abruption. They are at increased risk of preterm labour and of bearing macrosomic (>3999g) or low birth weight infants (<2500g). The women themselves typically believe that their age puts their infant at increased risk (Joseph et al, 2005). Unsurprisingly they have higher rates of obstetric intervention.
The Caesarean rate for nulliparous women over 35 years is 38% and 50% in women over 40 years (Joseph et al, 2005). In nulliparous women, the relationship between maternal age and delivery by emergency Caesarean is linear (Smith et al, 2008) which suggests a biological effect of advancing maternal age on labour performance, rather than simply obstetrician or maternal preference.
Antepartum stillbirth is particularly important in this group of women, because they are relatively unlikely to have future pregnancies. Induction before term is logical because, although the perinatal mortality rate is lowest at 41 weeks, the gestational age associated with the lowest cumulative risk of perinatal death is 38 weeks (Smith 2001). This is because the population at risk from continuing the pregnancy is all ongoing pregnancies rather than just the babies born that week. The largest increase in risk of stillbirth for women over 35 years of age starts at 39 weeks and peaks at 41 weeks. Women over 40 years old have a similar stillbirth risk at 39 weeks as women who are between 25 and 29 years old at 41 weeks, once they pass 40 weeks gestation their risk of stillbirth exceeds that of all women < 40 years old at term (Reddy et al, 2006). Primiparous women have a higher risk of stillbirth than multiparous women for all maternal age groups.
Obstetricians and parents generally understand this, but hold back from routine induction for fear of increasing caesarean sections.
Emergency caesarean sections carry an increased maternal morbidity and mortality compared to vaginal delivery and have consequences for future pregnancies (uterine rupture and placenta praevia). Caesarean sections cost £760 more than a vaginal delivery (Audit Commission report, 1997). A recent trial of induction of labour at term for women identified as high risk for emergency CS (higher the risk score, earlier the induction), found in the treatment group a similar CS rate, a higher vaginal birth rate and a reduced NICU admission and adverse outcome rate (Nicholson et al, 2008).
Perinatal deaths affect 0.8% of all pregnancies to women over the age of 35 years, and 1% of all pregnancies to women over the age of 40 years. The distribution of maternal age among the mothers having perinatal deaths is significantly higher than the general maternity population. Mothers having stillbirths and neonatal deaths are more likely to be older (40+ years). When an adverse event is rare, a large sample size is needed for a trial to prove that an intervention reduces the risk of that adverse event occurring.
Many obstetricians already induce older pregnant women at term (39% women aged 40-44, 58% women aged over 45), and many others believe that induction would improve perinatal outcomes but are reluctant to offer it for fear of increasing caesarean rates. However, it is equally plausible that induction might reduce caesarean section in which case an effective intervention is being under implemented.
There is a growing body of evidence that induction of labour at term does not increase emergency caesarean section rates and does not increase intrapartum deaths. In two other large multi-centre RCTs where induction of labour was compared with expectant management for term prelabour rupture of membranes (Hannah et al, 1996) and for post-term pregnancies (Gulmezoglu et al, 2007), a policy of induction did not increase the CS rate. More recently a large RCT comparing induction of labour (between 36 and 41 weeks) versus expectant management for women with gestational hypertension or mild pre-eclampsia (Koopmans et al, 2009) found that the rate of caesarean delivery was the same in both groups. Induction versus expectant monitoring for intrauterine growth restriction at term (Boers et al, 2010) a multi-centre RCT of 650 women found no difference in CS rates between the two groups.
Unfortunately there is no hard evidence to guide policy on induction of labour for advanced maternal age.
1.2 RATIONALE FOR CURRENT STUDY
The primary aim of this randomised controlled trial is to test the null hypothesis that a policy of induction of labour at 39 weeks gestation for nulliparous women over the age of 35 years reduces caesarean section rates. It will also enable us to collect data to test the feasibility of a larger study to test the effect of the policy of induction on perinatal death and serious neonatal morbidity. There is already evidence, albeit from non randomised studies, that such a policy would reduce adverse perinatal outcomes, in particular late stillbirth. The policy is not currently widely implemented because of fears that it would increase caesarean section rates. If induction of labour reduces the risk of intra-partum caesarean section then it would be adopted widely. This would almost certainly result in reduced late stillbirths at no maternal cost. We will also measure participants views about the two study arms to ensure that both are acceptable to women. This project provides an important opportunity to not only influence clinical practice in this important area, but to add to the increasing body of unbiased knowledge about the effects of policies of labour induction for various indications near term.
2. STUDY OBJECTIVES
1. To test the null hypothesis that a policy of induction of labour at 39 weeks for nulliparous women over the age of 35 years reduces the rate of emergency caesarean deliveries.
2. There is also a need for a much larger trial to answer the question, does induction of labour improve perinatal outcomes. This would be a large and costly trial, involving approximately 10,000 women. We will pilot this larger study, and measure:
The recruitment rate per hospital.
The age distribution of participating women.
Compliance with the treatment arms of the trial.
The overall gestational age distribution of the two groups.
Completeness of outcome data
3. STUDY DESIGN
Type of study: A multi-centre prospective randomised controlled trial
Duration: 24 months
Number and type of participants: 630 nulliparous pregnant women over 35 years of age
Recruitment and consent: Women will be identified in the antenatal period by their obstetrician or midwife. They will be offered an information sheet. They will be offered trial entry, and if they agree will sign a written consent. Women who are aged between 35-39 years at some of the participating centres will be community led care. Those women will be sent an invitation flyer or leaflet with their dating scan appointment to inform them of the trial and approached in person at their 20/40 anomaly scan at the hospital. Those women who express an interest in joining the trial will be seen by the research midwives/principal investigator at 36/40 for randomisation
Randomisation: Participants will be assigned to one of two treatment groups via a computerised randomisation programme at the Clinical Trials Unit, Nottingham University Hospitals NHS Trust. Randomisation will occur at 360/7 – 396/7 weeks gestation.
Interventions: Women will be randomly allocated to one of two groups
· Treatment group: Women over the age of 35 years with a singleton live fetus in a cephalic presentation will be assigned to induction of labour between 390/7 and 396/7 weeks gestation.
· Control group: Women over the age of 35 years with a singleton live fetus in a cephalic presentation will be assigned to expectant management i.e. awaiting spontaneous onset of labour unless a situation develops necessitating either induction of labour or Caesarean Section. Those without any medical indication for induction will be offered induction of labour anywhere between T+7 and T+14, the exact time to be determined by consultant’s usual practice. No additional monitoring in the expectant management group prior to T+14 should be offered unless it is the consultant’s usual practice. If the patient declines induction of labour at T+14 the patient will be offered a scan for growth and liquor volume and offered alternate day or daily CTG monitoring depending on the consultants usual practice.
This is a pragmatic clinical trial where individual units will be able to follow their own policies for induction of labour. Each unit will record their local prostaglandin and oxytocin regime and Bishop score cut-off for amniotomy, prior to entry to the trial. Once this is recorded staff should as far as possible use the same induction protocol for all participants and also for those women who for whatever reason require induction in the “await spontaneous labour” group.
3.1 Study outcome measures
The primary end point is caesarean section.
Secondary end points will include:
a) Maternal outcomes
Number of antenatal appointments from 36 weeks onwards
Community midwife
General Practitioner
Antenatal clinic
Mode of delivery
Vaginal delivery
Assisted vaginal delivery (forceps or ventouse)
Caesarean section
Type of practitioner performing the delivery
Midwife
Consultant Obstetrician
Staff Grade/Associate Specialist
Specialist Trainee
Other
If member of staff required to supervise the delivery: