An Investigation Into the Role of Previous in Labour Caesarean Section in Future Preterm Birth Risk and Management Strategies
Phase: NA
Conditions: Preterm Birth, Preterm Premature Rupture of Membrane, Preterm Spontaneous Labor With Preterm Delivery
Sponsor: Guy's and St Thomas' NHS Foundation Trust

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 1 of 38 
C   RAFT 
 
STUDY PROTOCOL 
CRAFT: Cerclage after full dilatation caesarean section; 
an investigation into the role of previous in labour caesarean section in future preterm birth 
risk and potential management strategies 
Co-sponsors 
Kings College London 
Professor Reza Razavi 
Vice President & Vice Principal (Research) 
King’s College London 
Room 5.31, James Clerk Maxwell Building 
57 Waterloo Road 
London SE1 8WA 
Telephone: +44(0) 207 8483224 
Fax: 02071888330 
Email:  reza.razavi@kcl.ac.uk 
Guy’s and St Thomas’ NHS Foundation Trust 
Elizabeth Bruna 
Guy’s and St Thomas’ Foundation NHS Trust 
R&D Department 
16th Floor Guy’s Hospital, Tower Wing,  
Great Maze Pond 
London SE1 9RT 
Ext tel: 02071889811 
Int tel: 89811 
Fax: 02071881295 
Email: R&D@gstt.nhs.uk 
Funder 
J.P. Moulton Charitable Foundation 
Chief Investigator 
Professor Andrew Shennan 
Department of Women and Children’s Health, St 
Thomas’ Hospital, London SE1 7EH 
andrew.shennan@kcl.ac.uk  
Co-Investigators 
Dr Lisa Story, Dr Natalie Suff, Dr Jenny Carter, Dr Jana 
Hutter, Professor Mary Rutherford, Professor Daniel 
Alexander, Dr Nigel Simpson, Professor Anna David, 
Mr Paul Seed, Dr Agnieszka Glazewska-Hallin 
Research Ethics number 
REC 19/LO/1270 
ISRCTN Number 
15068651 
Version number and date 
Version 1.0 01/04/2019 
Study Coordinator 
Dr Lisa Story/Dr Agnieszka Glazewska-Hallin  
Trial Statistician 
Mr Paul Seed 
Version and date of protocol amendments 
2.0 
 
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 2 of 38 
C   RAFT 
 
Name and address of Co-Investigator(s), Statistician, Laboratories etc. 
Name: Professor Mary Rutherford   
Address: Centre for the Developing Brain, Perinatal Imaging & Health, Imaging Sciences & 
Biomedical Engineering Division, King’s College London, 1st Floor South Wing, St Thomas’ Hospital, 
London SE1 7EH 
Email: mary.rutherford@kcl.ac.uk 
 
Name: Professor Daniel Alexander  
Address: University College London, Department of Computer Science, Gower Street, London, 
WC1E 6BT 
Email:  d.alexander@ucl.ac.uk 
 
Name: Professor Anna David 
Address: EGA Institute for Women’s Health, University College London, Room 244, Medical School 
Building, Huntley Street, London WC1E 6AU 
Email: a.david@ucl.nhs.uk 
 
Name: Dr Nigel Simpson 
Address: Delivery Suite, C Floor, Clarendon Wing, The General Infirmary at Leeds, Belmont Grove, 
Leeds LS2 9NS 
Email: N.A.B.Simpson@leeds.ac.uk 
 
Name: Dr Lisa Story  
Address: Centre for the Developing Brain, King’s College London, 1st Floor South Wing, St Thomas’ 
Hospital, London SE1 7EH 
Telephone: 0207 188 9145 
Fax: 0207 188 9154 
Email: lisa.story@kcl.ac.uk 
 
Name: Dr Natalie Suff 
Address: Department of Women and Children’s Health, 10th Floor North Wing, St Thomas’ 
Hospital, London SE1 7EH 
Telephone: 020 7188 3634 
Email: natalie.suff@kcl.ac.uk 
 
Name: Dr Agnieszka Glazewska-Hallin 
Address: Department of Women and Children’s Health, 10th Floor North Wing, St Thomas’ 
Hospital, London SE1 7EH 
Telephone: 020 7188 3634 
Email: agnieszka.glazewska-hallin@kcl.ac.uk 
 
Name: Mr Paul Seed, Senior Statistician 
Address: Department of Women and Children’s Health, 10th Floor North Wing, St Thomas’ 
Hospital, London SE1 7EH 
Telephone: 020 7188 3639 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 3 of 38 
C   RAFT 
Email: paul.seed@kcl.ac.uk 
 
Name: Dr Jana Hutter  
Address: Centre for the Developing Brain, King’s College London, 1st Floor South Wing, St Thomas’ 
Hospital, London SE1 7EH 
Email: jana.hutter@kcl.ac.uk 
 
Name: Dr Jenny Carter 
Address: Department of Women and Children’s Health, 10th Floor North Wing, St Thomas’ 
Hospital, London SE1 7EH 
Telephone: 020 7188 3634 
Email: jenny.carter@kcl.ac.uk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 4 of 38 
C   RAFT 
STUDY SYNOPSIS 
 
Title of clinical trial 
 
 
An investigation into the role of previous in labour caesarean section in future 
preterm birth risk and management strategies 
Protocol Short Title/Acronym  
CRAFT: Cerclage after full dilatation caesarean-section 
Study Phase if not mentioned 
in title 
 
Not applicable  
Sponsor name 
 
King’s College London and Guy’s and St Thomas’ Hospital  
Chief Investigator 
 
 
Andrew Shennan, Department of Women and Children’s Health, King’s College 
London  
0207188 3639 
Andrew.shennan@kcl.ac.uk 
REC number 
 
19/LO/1270 
 
Medical condition or disease 
under investigation 
 
Increased risk of preterm birth following previous caesarean section in labour 
Purpose of clinical trial 
 
 
CRAFT-OBS: Observational Study; To evaluate subsequent pregnancy risk of 
preterm birth in women with a history of previous caesarean in established 
labour. This prospective study using clinically acquired cervical length and 
quantitative fetal fibronectin data will help establish a predictive model of 
preterm birth <34 weeks and <37 weeks. 
CRAFT-RCT: Randomised controlled trial arm; To assess treatment for short 
cervix in women at high risk of preterm birth following a caesarean section at 
fully dilated 
CRAFT-IMG: Imaging sub-study; To aid understanding of micro and 
macrostructural features within the cervix which predisposes to preterm birth 
in women with a previous full dilatation caesarean section. This will use MRI 
and an advanced transvaginal ultrasound protocol and to assess if structural 
changes can be visualised in the cervix. 
Primary objective 
 
 
1. CRAFT-OBS: To assess the risk of preterm birth or late miscarriage in 
women following an in labour caesarean section  
2. CRAFT-RCT: To assess if cervical cerclage reduces preterm birth in 
pregnant women with a short cervix following a previous in labour 
caesarean section 
3. CRAFT-IMG: To assess if alterations in MRI parameters or ultrasound 
characteristics occurs in women who undergo a late miscarriage or 
preterm birth following an in labour caesarean section. 
Trial Design  
 
Prospective observational study, nested randomised controlled trial and 
imaging sub-study in a selected cohort 
Endpoints 
 
Incidence of preterm birth at < 34 weeks gestation 
Sample Size 
 
 
CRAFT-OBS: 2200 women, CRAFT-RCT: 1000 women, CRAFT-IMP: 60 women 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 5 of 38 
C   RAFT 
Summary of eligibility criteria 
 
 
CRAFT-OBS: pregnant women 14+0-23+6 week with a previous history of 
caesarean section in labour. 
CRAFT-RCT: pregnant women with a previous history of caesarean section 
carried out at full dilatation and a short cervix (25mm) in current pregnancy.  
CRAFT-IMG:  pregnant women with a previous history of caesarean section 
carried out at full dilatation (30 women with cervix >25mm; 30 CRAFT-RCT 
participants). 
Maximum 
duration 
of 
treatment of participant 
 
Until delivery or removal of cerclage at 37 weeks gestation 
Version and date of final 
protocol 
 
Version 2.0 (10/09/19) 
Version and date of protocol 
amendments  
 
To be inserted 
 
 
 
Figure 1: Flow of participants through CRAFT project 
 
 
 
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 6 of 38 
C   RAFT 
Contents 
STUDY SYNOPSIS ............................................................................................................................................................... 4 
LAY SUMMARY ................................................................................................................................................................... 8 
PROFESSIONAL SUMMARY ............................................................................................................................................ 8 
GLOSSARY OF TERMS .................................................................................................................................................... 11 
1. 
Introduction ............................................................................................................................... 12 
1.1. 
Background ....................................................................................................................................... 12 
1.2. 
Rationale for study ......................................................................................................................... 13 
 
Study aims and objectives ..................................................................................................... 15 
2. 
 
2.1. 
Aims ..................................................................................................................................................... 15 
2.2. 
Study objectives ................................................................................................................................. 15 
2.2.1. 
CRAFT-OBS: a study of risk and management in women with a history of CS in labour ...... 15 
2.2.2. 
CRAFT-RCT: a trial of USS indicated cerclage in women with history of FDCS ....................... 16 
2.2.3. 
CRAFT-IMG: a sub-study evaluating imaging methods for assessing risk and management of 
women with a history of FDCS......................................................................................................................... 16 
3. 
Study Design ................................................................................................................................. 16 
3.1. 
CRAFT-OBS ........................................................................................................................................... 16 
3.2. 
CRAFT-RCT ........................................................................................................................................... 16 
3.3. 
CRAFT-IMG .......................................................................................................................................... 17 
3.4. 
Expected study duration ................................................................................................................... 17 
4. 
Study Endpoints ........................................................................................................................... 17 
4.1. 
CRAFT-OBS ........................................................................................................................................... 17 
4.2. 
CRAFT-RCT ........................................................................................................................................... 18 
4.3. 
CRAFT-IMG .......................................................................................................................................... 18 
5. 
Sample size and power calculation .......................................................................................... 19 
6. 
Participant inclusion and exclusion criteria ............................................................................ 20 
6.1. 
Inclusion and exclusion criteria for ALL CRAFT participants ...................................................... 20 
6.2. 
Inclusion and exclusion criteria specific to CRAFT-RCT ............................................................... 20 
6.3. 
Inclusion and exclusion criteria specific to CRAFT-IMG .............................................................. 20 
7. 
Study procedures ......................................................................................................................... 21 
7.1. 
Identification of participants ........................................................................................................... 21 
7.2. 
Consent procedure ............................................................................................................................. 23 
7.3. 
Data Collection ................................................................................................................................... 23 
7.4. 
Trial intervention and additional imaging (CRAFT-RCT and CRAFT-IMG) ................................ 25 
8. 
Data analysis ................................................................................................................................. 26 
9. 
Study Governance ........................................................................................................................ 27 
9.1. 
Ethics & Regulatory Approvals ........................................................................................................ 27 
9.2. 
Assessment of Efficacy for MRI and transvaginal ultrasound .................................................... 28 
9.3. 
Procedures for Assessing Efficacy Parameters ............................................................................. 28 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 7 of 38 
C   RAFT 
9.4. 
Specification, Timing and Recording of Safety Parameters ....................................................... 28 
 
Safety .................................................................................................................................................... 28 
9.5. 
28 
9.6. 
Trial Management Group ................................................................................................................. 30 
9.7. 
Trial Steering Committee (TSC) ........................................................................................................ 31 
9.8. 
Data Monitoring Committee (DMC) ............................................................................................... 31 
9.9. 
Study Coordinating Centre ............................................................................................................... 31 
9.10. 
Trial stopping rules ............................................................................................................................ 31 
10. 
Investigator responsibilities ....................................................................................................... 32 
10.1. 
Data Handling ..................................................................................................................................... 32 
10.2. 
Data Sharing ........................................................................................................................................ 32 
10.3. 
Linkage of data ................................................................................................................................... 33 
10.4. 
GCP Training ........................................................................................................................................ 33 
10.5. 
NHS Trust Research and Development .......................................................................................... 33 
10.6. 
Protocol amendments ....................................................................................................................... 33 
10.7. 
Protocol violations and deviations ................................................................................................. 34 
10.8. 
Direct access to source data and documents ................................................................................ 34 
11. 
Finance ........................................................................................................................................... 34 
12. 
Publication Policy ......................................................................................................................... 34 
13. 
Insurance and Indemnity ............................................................................................................ 34 
14. 
Signatures ................................................................................................................................... 35 
 
 
 
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 8 of 38 
C   RAFT 
LAY SUMMARY 
 
Worldwide, there is a 9.6% rate of preterm birth before 37 weeks. The timing of preterm birth is 
directly related to the amount of risk to the infant at birth and for his/her long-term health. Very 
early preterm deliveries under 28 weeks gestation carry more risk for the development of the 
infant’s lungs, risk of cerebral palsy, and eye problems just to name a few; not to mention the 
repercussions for parents supporting their infants in neonatal care at a detriment to the 
remaining family dynamics.  
 
There are multiple factors which predispose women to preterm birth such as surgery to the neck 
of the womb, previous preterm birth and multiple pregnancies. A new factor now found to be 
contributing to this risk is if the mother has had a previous full dilatation caesarean section (FDCS) 
in labour particularly when she is 10cm dilated. We don’t know how significant this risk is in the 
UK and the mechanism is not proven but what is known is that it particularly affects pregnancies 
under 28 weeks and also results in many late miscarriages (14-23+6 weeks). It is thought it occurs 
because a cut is made to the cervix (neck of the womb) at the time of the caesarean which 
weakens it. We do not routinely look for a scar on transvaginal ultrasound when measuring the 
cervical length (CL).  
 
New NHS Commissioning guidelines(1) and Saving Babies Lives Care Bundle(2) has now 
recommended to screen all women with a previous FDCS because of this new widely reported 
risk. We don’t know whether a cerclage (stitch) inserted into the cervix, first line prophylactic 
treatment in many UK units for a short cervix (25mm), works in this group of women. We have 
never imaged the cervix looking for injury in this FDCS group of women and compared it to our 
assessment with routine transvaginal ultrasound. We also do not know if a cut off of 25mm is a 
short cervix in women with a previous FDCS. Furthermore, we do not know how many women 
with a previous caesarean at 4-9cm dilatation has a risk of preterm birth in the future nor if our 
current tests of cervical length and fibronectin test work well to predict preterm birth in these 
women. A cerclage for a short cervix 25mm in women with a previous FDCS is not part of routine 
care. Hence why there is a three-pronged approach in CRAFT:  
 
1. Observational study of women with a previous caesarean in labour  
2. A randomised trial of women with a previous FDCS being treated with and without a cerclage 
if their cervix is short (25mm) 
3. Imaging sub-study using transvaginal ultrasound and magnetic resonance imaging (MRI) to 
characterise any scars found to try to work out the mechanism of the problem. 
 
PROFESSIONAL SUMMARY 
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 9 of 38 
C   RAFT 
Preterm birth (PTB), birth before 37 weeks gestation, has a global prevalence of 9.6% and over a 
million annual neonatal deaths. Recently, it has been observed FDCS are associated with 
recurrent, early premature births and late miscarriage (LM). Over 25% of all deliveries in the UK 
are by caesarean section (CS) and at least one in seven of these occur at full dilatation, affecting 
20,000 women per year. These women have a six-fold increased incidence of subsequent 
preterm birth compared with women who undergo 1st stage CS earlier in labour, which equates 
to 2500 women per year in the UK. In women who lose a pregnancy, more than half will also go 
on to experience recurrent pregnancy losses in spite of current intervention. Prediction and 
management of these cases requires further understanding of its aetiology, assessment of 
current prediction strategies as well as clinical management. 
 
Despite the emerging association between FDCS and the risk of PTB/LM, the risk following  an in 
labour CS, not at full dilatation, is unknown. It is thought that late stage caesareans, from 7cm 
onwards, are likely to carry some risk of future preterm birth (3). Furthermore, our current 
predictive models of preterm birth based on transvaginal ultrasound and quantitative fetal 
fibronectin are not validated in this specific cohort of women. In this CRAFT study we will evaluate 
the risk of preterm birth in women with a previous history of caesarean section in labour. 
 
Clinically, a short cervix (25mm) on transvaginal ultrasound scan (TVS) during the second 
trimester identifies women at high risk of PTB/LM.  These women may benefit from prophylactic 
treatment such as a cervical cerclage but currently it is not part of routine care. At present it is 
unknown whether the 25mm cut-off is a reliable predictive measure of risk in women following 
in labour CS. The mechanism of late miscarriage and early premature births <34 weeks needs to 
be further understood with the imaging modalities available to us.  
 
There will be three components to the CRAFT project: 1) CRAFT-OBS 2) CRAFT-RCT and 3) CRAFT-
IMG Study 
 
CRAFT-OBS: a study of risk and management in women with a history of CS in labour 
We will screen all pregnant women with a history of caesarean section in labour booked for 
maternity care at all participating sites with transvaginal ultrasound and quantitative fetal 
fibronectin (if available) between 14+0 and 23+6 weeks with a previous in labour CS. These women 
will be grouped into: 
 
1. Unknown dilatation at time of CS in labour. 
2. Dilated 4cm to 9cm at time of CS in labour. 
3. Full dilatation at time of CS in labour. 
 
This part of the project will allow us to: 
 
1. Determine pregnancy outcomes in women who have had previous in-labour CS. 
2. Evaluate risk of PTB/LM according to degree of dilatation in previous in-labour CS. 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 10 of 38 
C   RAFT 
3. Evaluate the predictive value of quantitative fetal fibronectin in women with previous CS 
in labour if done by direct care team for clinically indicated reasons at any point 
4. Evaluate the predictive value of transvaginal ultrasound and whether cervical defects can 
be identified if performed by direct care team for clinically indicated reasons at any point. 
5. Identify women who require referral into specialist preterm surveillance clinics. 
6. Identify potential participants for CRAFT-RCT (see Figure 1). 
 
 
CRAFT-RCT: a trial of USS indicated cerclage in women with history of FDCS 
The aim of this trial is to evaluate efficacy of cervical cerclage in pregnant women with a short 
cervix (25mm) on TVS between 14+0 and 23+6 weeks gestation following a FDCS.  The study will 
allow us to  evaluate the impact of cervical cerclage on: 
 
1. Primary obstetric outcome – spontaneous preterm birth rate <34 weeks gestation. 
2. Secondary outcomes - Short-term pregnancy and neonatal outcomes, including a 
composite of neonatal death and morbidity. 
 
CRAFT-IMG: a study evaluating imaging methods for assessing risk and management of women 
with a history of FDCS 
This imaging sub-study will focus on analysis of TVS and magnetic resonance imaging (MRI) of 
cervical defects in this population to elucidate which women are at increased risk of PTB/LM. 
Assessment of any identified cervical defect and its relation to a cervical cerclage will also help 
us to establish which women at risk of PTB would benefit from this treatment. 
 
Objectives of the imaging study: 
 
1. To assess whether cervical abnormalities can be visualised in the cervix by TVS and MRi. 
2. To determine which women in this FDCS cohort are most at risk of preterm birth. 
3. To identify which women with a previous CS in established labour are most likely to 
benefit from a cervical cerclage. 
 
Investigating the mechanism underpinning the increased risk of PTB/LM will aid our 
understanding of risk in women with a history of FDCS only and inform current and future 
treatment strategies. We will recruit 30 women with a CL of >25mm and 30 women with a CL of  
25mm (short cervix).  Women with a short cervix will be participants of the main RCT. Half of 
these women will have had a cervical cerclage as part of their management.  
 
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 11 of 38 
C   RAFT 
GLOSSARY OF TERMS 
 
FDCS 
Fully dilated caesarean section 
CS 
Caesarean section 
MRI 
Magnetic Resonance Imaging 
PTB 
Preterm Birth 
LM 
Late miscarriage 
TAC 
Transabdominal cerclage 
CL 
Cervical length 
qfFN 
Quantitative fetal fibronectin 
 
 
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 12 of 38 
C   RAFT 
1. Introduction 
1.1. Background 
Preterm birth (PTB), defined as birth less than 37+0 weeks gestation, is a significant health issue 
and is the most important single determinant of adverse infant outcome with regards to survival 
and quality of life(4). Morbidity is inversely correlated to gestational age, and the most significant 
adverse outcomes are associated with very preterm birth, defined as occurring less than 32+0 
weeks gestation. Preventative measures which prolong fetal gestation by 1 week, such as those 
proposed by this study, could save health services £939 million per year in England and Wales(5). 
 
The insertion of a suture around the cervix under regional anaesthesia is an established 
management strategy in those women at high risk of preterm birth. There is little consensus on 
the optimal procedure, technique or timing of insertion. Its mechanism of action has been 
hypothesised as not only supportive but as reinforcing the immunological barrier which protects 
the fetus from ascending vaginal infection. The benefit of an ultrasound indicated cerclage 
following evidence of cervical shortening (25mm) on transvaginal ultrasound scan has been 
reported to demonstrate a significant reduction in delivery <35 weeks gestation compared with 
expectant management (6). 
 
The primary risk factor for PTB in multiparous women is a previous PTB(7). Emerging evidence 
has shown an association between late miscarriage (LM) (14-24 weeks) and PTB in women with 
a history of full dilatation caesarean section (FDCS) at term, affecting approximately 13.5% of 
these women. This is hypothesised to be due to a uterine incision, which is inadvertently too low, 
in or near to effaced cervical tissue.  This occurs because the cervix becomes continuous with the 
lower segment of the uterus at full dilatation and the anatomy can often be distorted.  Disruption 
and scarring of this cervical tissue is thought to result in cervical incompetence in future 
pregnancies. The association between FDCS and LM/PTB has only recently been recognised and 
it presents a pressing clinical problem.   
 
Over 25% of all deliveries in the UK are by CS and up to 20% of in labour caesarean sections occur 
at full dilatation, which could affect up to 20,000 women in the UK per annum (8). These women 
have a six-fold increased incidence of subsequent preterm birth compared with women who 
undergo CS in the first stage of labour (adjusted odds ratio 5.8; 95% confidence interval 1.08-
30.8)(3); 13.5% in comparison with 2%.  This equates to around 2500 women per year in the UK. 
In women who lose a pregnancy, more than half will also go on to experience recurrent 
pregnancy losses in spite of intervention, compared to 14% of women with a history of preterm 
birth without previous FDCS (relative risk 3.06 95% confidence interval 1.22-7.71)(9).  The relative 
risk of PTB in women with a previous emergency CS earlier in labour is unknown, however it is 
thought to be a continuum of risk, i.e. the later in labour the CS is carried out, the higher the risk 
of PTB in future pregnancies.  
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 13 of 38 
C   RAFT 
A screening programme to assess for cervical shortening in women with a previous FDCS is due 
to be implemented as part of new NHS commissioning guidance(1) and the revised Saving Babies 
Lives Care Bundle(2). It is unknown whether transvaginal cervical length screening for a short 
cervix predicts outcome in this group and there is currently limited evidence to inform optimal 
management of these women. It is also unknown whether first-line interventions for short cervix 
25mm (vaginally-placed cerclages inserted in the distal cervix during pregnancy), used in other 
high-risk groups of women, is effective in this cohort.  Preliminary data indicates that these 
interventions may be less efficacious, likely due to the injury having occurred in the proximal 
cervix, above the cerclage. A small retrospective analysis indicated that of 19 women who had 
experienced a LM/PTB subsequent to a FDCS and who then had a cerclage in the 3rd pregnancy, 
10 (53%) still delivered <30 weeks gestation in comparison with 3% of a high-risk control group, 
who also had a cervical cerclage in situ after a LM/PTB (n=154). 
This study has been developed in collaboration with the Preterm Birth Studies PPI Group at St 
Thomas’ Hospital.  They have confirmed that this issue is of vital importance to them and they 
will be consulted on all study literature and future directions associated with this project. 
1.2. Rationale for study 
The overall aim of the CRAFT project is to investigate the role of previous in labour caesarean 
section in future preterm birth risk and management strategies.  
CRAFT-OBS will determine the risk of spontaneous PTB in women with previous CS in labour. We 
will use any data on qfFN testing and CL measurements to validate current predictive modelling 
of preterm birth using these tests, which are the most commonly used predictors of PTB. 
Participants whose CS was carried out at full dilatation, and whose cervix measures ˂25mm will 
also be invited to take part in the CRAFT-RCT (n=1000) and CRAFT-IMG (n=30). Participants with 
a history of FDCS and a cervix ≥25mm will be offered the opportunity to participate in CRAFT-
IMG (n=30).   
CRAFT-RCT will determine whether an ultrasound-indicated cervical cerclage is an effective 
management option in women with cervical shortening following a FDCS.  It will also determine 
if a shortening cervix predicts outcome in this cohort. If it is demonstrated to be ineffective, 
further research will be required regarding alternative screening and treatment options. This may 
include imaging the cervix pre-pregnancy for evidence of cervical defects and/or offering a 
transabdominal cerclage (TAC) in the proximal cervix pre-pregnancy above the level of 
hypothesised defects.  
  
CRAFT-IMG will inform development of methods for identifying cervical defects in women with 
a history of CS in labour.  We will explore the value of scanning the cervix for scars/areas of 
abnormality to indicate which women are most at risk of adverse outcomes and require further 
monitoring and therapy. Currently the ultrasound-assessed CL is the only parameter used in 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 14 of 38 
C   RAFT 
clinical practice to guide management of women at high risk of PTB and this has not been 
validated in women with previous FDCS.  There is a need to evaluate the features of the cervix 
and any scar tissue by both MRI and US to evaluate which characteristics can accurately 
determine which women are likely to go on to experience LM/PTB.  Preliminary data indicates 
that scars can be consistently identified on ultrasound and their location defined in relation to 
the internal-os of the cervix. MRI can provide additional information regarding tissue 
microstructure.  Previous studies have indicated that changes in signal intensity of cervical 
stromal layers have been found on T2 weighted images(10) and alterations in basic diffusion 
imaging (a measure of Brownian motion of water molecules in tissue enabling assessment of 
microstructure) with relation to the onset of labour reported(11).  This will help evaluate the 
value of imaging and our ability to predict who will need a cerclage – for example location of scar 
from FDCS.  
The development of sophisticated diffusion techniques such as Intravoxel Incoherent Motion 
(IVIM), has enabled assessment of tissue microstructure, diffusivity and perfusion(12). This 
separates diffusion perfusion from true diffusion effects, the signal decay is described by a 
biexponential instead of a mon-exponential equation which yields a more accurate description 
of the underlying tissue properties(13). This technique has been used to assess perfusion in 
cervical carcinoma(14) but has not been investigated in relation to PTB. Professor Daniel 
Alexander (UCL), a world leading expert in the field of diffusion MR imaging, has previously 
harnessed these techniques in the assessment of the breast, brain, placenta, and prostate. In this 
project, his team will facilitate optimal data acquisition and analysis of the cervix using IVIM.
 
 
Pilot Data 
Figure 
1: 
preliminary 
data 
demonstrating the basic quantification 
of cervix microstructure with MRI.  A 
cervical defect can be seen ex-vivo from 
a pathology specimen of a uterus and 
cervix where the patient had previously 
undergone a full dilatation caesarean 
section (a).  MRI imaging shows a similar 
cervical defect (b).  The left image is T2 
weighted and apparent diffusion co-
efficient (ADC) map and fractional 
anisotropy (FA) maps, both reflecting 
tissue structure can be seen in the centre and 
right images.  The cervical defect is indicated 
with the left arrows.  The right arrows 
indicate the cervical canal.  
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 15 of 38 
C   RAFT 
 
Defects in the cervix have already been identified by our research group in non-pregnant women 
who have undergone LM/PTB following a FDCS using MRI. These lesions are comparable to 
pathology specimens of women with a similar history (see Figure 1).   
 
Ultrasound is a commonly used modality in obstetrics to quantify the CL. The CS scar can be easily 
identified in the lower uterine segment or cervical tissue using transvaginal ultrasound 
examination. Using Doppler ultrasound the internal os is identified relative to the height of the 
uterine arteries bilaterally as they traverse lateral to the cervix (methodology developed by 
Professor Anna David at University College London Hospitals). The scar defect position has been 
studied prospectively in women with a previous FDCS who booked at University College London 
Hospital. Results in 87 women seen over 14 months found a 37% rate of PTB in 8 women whose 
scar defect was ≥5mm from the internal os or within the cervix itself, compared to 5% of 21 
women whose scar defect was >5mm above the internal os. We will use the same methodology 
in this trial and imaging study.  We will also analyse inter/intra-observer variation in performing 
cervical ultrasound assessment and compare it to MRI images. 
 
 
2. Study aims and objectives 
2.1. Aims 
There are three overall aims of the CRAFT project which correspond to each distinct part: 
  
i. 
To understand the association between the degree of cervical dilatation at CS in labour 
with risk of LM/PTB in subsequent pregnancies.  
ii. 
To assess the efficacy of cervical cerclage for a short cervix 25mm detected by 
transvaginal ultrasound in a randomised controlled trial of women with previous FDCS 
(CRAFT-RCT). 
iii. 
To identify a mechanism for the increased risk of preterm birth with MRI and transvaginal 
ultrasound in order to predict those at most risk and whether cervical cerclage would be 
of benefit (CRAFT-IMG) 
 
 
2.2. Study objectives 
2.2.1. CRAFT-OBS: a study of risk and management in women with a history of CS in 
labour 
 
i. Determine the incidence of LM and PTB (prior to 37 weeks) in women with previous CS in 
labour stratified by cervical dilatation. 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 16 of 38 
C   RAFT 
ii. If ultrasound measured cervical length and quantitative fibronectin are carried out, this 
data will be collated and help evaluate the ability of these tests to determine risk of preterm 
birth in women with a history of in labour caesarean. 
 
 
2.2.2. CRAFT-RCT: a trial of USS indicated cerclage in women with history of FDCS 
 
i. Determine if an ultrasound-indicated cervical cerclage is effective management in women 
with a history of FDCS and cervical shortening (˂25 mm) in preventing LM or PTB <34 weeks 
gestation. Evaluate the impact of intervention on short-term fetal and neonatal outcomes, 
assessed as a composite of fetal and perinatal death and major morbidity. 
ii. Assess the impact of both management strategies (i.e. cerclage and observation) on health 
economic outcomes for mother and infant in terms of number of nights in hospital; cost 
data to hospital discharge/28 days post delivery. 
 
2.2.3. CRAFT-IMG: a sub-study evaluating imaging methods for assessing risk and 
management of women with a history of FDCS 
 
i. Ascertain whether MRI or ultrasound (or a combination of the two) can accurately predict 
PTB when abnormalities are detected in the cervix. 
ii. Identify which women are most likely to benefit from intervention. 
 
3. Study Design  
3.1. CRAFT-OBS  
This is a multicentre prospective cohort observational study of 2200 pregnant women with a 
previous history of CS in labour who will be recruited following their booking or scanning visit 
(Appendix: participating sites). Women who have had a previous FDCS and who are found to have 
a CL 25mm on transvaginal ultrasound will be offered recruitment to the CRAFT-RCT (see 
below). Women with a previous FDCS and a CL ≥ 25mm may be invited to participate in CRAFT-
IMG. If patients have a clinically indicated transvaginal cervical length or qfFN during their 
pregnancy, this information will also be collected. 
 
3.2. CRAFT-RCT 
This is a multicentre randomised controlled trial (RCT), carried out over 27 months in at least 41 
hospitals performing surveillance (n=1000).  All women with a history of FDCS will have CL 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 17 of 38 
C   RAFT 
monitoring as per new guidance <24 weeks(1). If their cervical length is or becomes ˂25 mm they 
will be randomised (1:1) into one of two groups:  
 
• cervical cerclage plus standard management  
• standard management 
  
3.3. CRAFT-IMG 
This is a prospective cohort sub-study collecting image data and outcomes in a sub-group of 
women participating in CRAFT-OBS (n=30) and CRAFT-RCT (n=30). 
 
The subgroup will be recruited from participants attending University College London and St 
Thomas’ Hospital only. All participants will have experienced FDCS in a previous pregnancy and 
will include women with and without cervical shortening in the current pregnancy based on their 
CL monitoring. Participants will be allocated to one of three groups: a) women with cervical 
length of ˂25 mm who have been randomised to cerclage in CRAFT-RCT (n=15), b) women with 
cervical length of ˂25 mm who have been randomised to observation in CRAFT-RCT (n=15),  c) 
women with cervical length of ≥25 mm.  
 
A transvaginal ultrasound using a new enhanced protocol developed by Professor Anna David at 
UCL will be undertaken in all women. This procedure is more detailed than standard 
measurement of CL. The site of previous scar tissue and any other abnormalities (for example 
the presence of cysts) will be recorded.  Serial MRIs will also be performed. Recruited patients 
will have up to 3 serial transvaginal ultrasounds and MRIs during their pregnancy. 
 
3.4. Expected study duration 
 
Recruitment will be conducted over a 24 month period.   The end of the study will be defined as 
28 days post-delivery or discharge from hospital (whichever sooner) of the last recruited 
participant and infant. Women will be followed-up until postnatal discharge.  The end of the 
study will be reported to the REC and Regulatory Authority within 90 days, or 15 days if the study 
is terminated prematurely.    
 
4. Study Endpoints  
4.1. CRAFT-OBS 
Primary endpoint: 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 18 of 38 
C   RAFT 
i) 
Delivery < 37 completed weeks gestation (powered).  
  
Secondary endpoints  
i) 
Adverse perinatal outcome, defined as a composite outcome of death 
(antepartum/intrapartum stillbirths plus neonatal deaths prior to discharge from 
neonatal services)  
ii) 
Delivery <34 weeks gestation.  
iii) 
Gestation at delivery. 
iv) 
Late miscarriage (14+0-23+6 weeks).  
v) 
Healthcare use, e.g. appointments, hospital admission, cervical length, cervicovaginal 
fetal fibronectin levels, interventions.  
vi) 
Predictive modelling to evaluate the ability of CL and fFN to determine risk of preterm 
birth <34 and <37 weeks  
vii) 
Other maternal and fetal morbidities, as per COPOP core outcome set for preterm 
birth intervention studies(15). 
 
4.2. CRAFT-RCT 
 
Primary endpoint: 
 
i. 
Delivery  <34 weeks gestation (powered) 
 
Secondary endpoints: 
 
i. 
Adverse 
perinatal 
outcome, 
defined 
as 
composite 
outcome 
of 
death 
(antepartum/intrapartum stillbirths plus neonatal deaths prior to discharge from 
neonatal services) or one/more of intraventricular haemorrhage, periventricular 
leukomalacia, 
hypoxic 
ischaemic 
encephalopathy, 
necrotizing 
enterocolitis, 
bronchopulmonary dysplasia and sepsis. 
ii. 
Gestation at delivery. 
iii. 
Requirement for rescue cerclage (bulging fetal membranes). 
iv. 
Time between intervention and delivery. 
v. 
Health costs at 28 days post-delivery. 
 
4.3. CRAFT-IMG 
 
Primary endpoint: 
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 19 of 38 
C   RAFT 
i. 
Alterations in imaging parameters between women with a full dilatation C-section in 
a previous pregnancy and either a cervix 25mm or a cervix >25mm in this pregnancy 
which culminates in a preterm (<37 week) delivery.   
 
 
5. Sample size and power calculation 
All power calculations were performed by the trial statistician Paul Seed. 
 
CRAFT-OBS: With estimated prevalence of 15% preterm birth rate prior to 37 weeks, and 16.2% 
of all deliveries being by emergency caesarean section; we will require data on 2200 women to 
estimate the event rate to 10% relative accuracy (e.g. 13.5% to 15.6%).  
An average district general hospital has 4,000 deliveries per year, of which 648 (16.2%) might be 
by Emergency Caesarean. We aim to recruit 324 of these (50%) at a minimum of 7 study sites. At 
St Thomas’ Hospital rather fewer deliveries (11%) are caesareans in labour; so we will aim for at 
least 20 sites, taking the assumptions above into account. 
If we acquire data of cervical length and/or quantitative fetal fibronectin in this cohort, we will 
be able to validate these prediction tools. If we treat a short cervix of 25mm, and a raised qfFN 
of >=50ng/ml as positive tests, we anticipate a 75% sensitivity and 83% specificity from the 
literature for both tests (16). 
Assuming 10% event rate, 1000 women (100 cases and 900 controls) would allow use to estimate 
the sensitivities of qfFN and CL to within 10% and the specificities to within 3% of the true value. 
The PPV would be estimated within 7% and NPV within 1.5% of their true values. 
CRAFT-RCT: Pilot data indicates that at least 10% of all births and 70% of preterm births 
associated with FDCS occur before 34 weeks. In order to detect a reduction in this rate from 10% 
to 5% 474 women are required in each group to give 80% power. We will aim to recruit 500 in 
each arm in order to allow for 5% loss to follow-up. 
 
CRAFT-IMG:  We consider that the participation of 60 women in this sub-study will provide useful 
information for planning future research; this is achievable by recruiting at 2 sites (UCLH and St 
Thomas’ Hospital): 30 women with cervix >25mm and 30 women with cervix 25mm  (15 women 
with cerclage, 15 women without). 
 
If we have data from participants in this study of their cervical length and/or quantitative fetal 
fibronectin we will be able to carry out predictive statistics. This would involve calculating ROC 
curves for prediction of spontaneous preterm birth for both fibronectin and transvaginal cervical 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 20 of 38 
C   RAFT 
length measurement as a continuous variable, for delivery <24, <30, <34 and <37 weeks 
gestation. From the optimal thresholds, predictive statistics will be calculated. 
 
6. Participant inclusion and exclusion criteria 
6.1. Inclusion and exclusion criteria for ALL CRAFT participants 
Inclusion criteria:  
• Pregnant women under 23+6 weeks gestation with a history of previous caesarean section 
in labour. 
• Singleton pregnancy. 
• Willing and able to give informed consent (with or without interpreter). 
Exclusion criteria:  
• Under 16 years of age. 
• Inability to give informed consent. 
• Previous caesarean section carried out before labour. 
• Women who have been commenced on management with progesterone, a cerclage or 
arabin pessary as part of their care or another research study 
 
6.2. Inclusion and exclusion criteria specific to CRAFT-RCT 
 
Inclusion criteria:  
• Pregnant women between 14+0 and 23+6 weeks gestation with a history of FDCS. 
• Short cervix (25mm) on transvaginal ultrasound scan. 
Exclusion criteria:  
• Women with persistent fresh vaginal bleeding evident on speculum examination.  
• Women with visible fetal membranes evident on speculum examination or open cervix 
on ultrasound scan.   
• Women with severe abdominal pain/evidence of sepsis (as judged by attending clinician).  
• Known significant congenital or structural or chromosomal fetal abnormality.  
• Suspected or proven rupture of the fetal membranes at the time of recruitment.  
 
6.3. Inclusion and exclusion criteria specific to CRAFT-IMG 
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 21 of 38 
C   RAFT 
Inclusion criteria: 
 
• Pregnant women between 14+0 and 23+6 weeks gestation with a history of FDCS. 
 
Exclusion criteria: 
 
• Contraindications to MRI, e.g. claustrophobia, BMI >40 kg/m2 (due to technical 
limitations of scanner) or a women with a non-MRI compatible metallic implant. 
 
7. Study procedures 
 
7.1. Identification of participants  
 
CRAFT-OBS 
 
We will recruit pregnant women who are booked for their delivery at participating centres who 
provide written informed consent to participate in the study and who meet the study eligibility 
criteria.  
 
Women who have previously had an emergency caesarean in labour will be identified through 
their booking appointment or scan appointments by the direct care midwife, doctor, 
sonographer and approached with information about this observational study. Clinical midwives, 
doctors or sonographers will highlight eligible women to the research team. The research team 
will then be able to discuss the research with patients if they are eligible at the time of their first 
trimester or second trimester scan. 
 
CRAFT-RCT 
 
Women participating in CRAFT-OBS will be eligible for CRAFT-RCT if they are found to have a 
cervix 25mm prior to 23+6 weeks gestation with a history of FDCS. Women with a previous full 
dilatation caesarean section will be identified by a member of the direct care team and referred 
for cervical surveillance as per new guidance (1,2). The research team will check relevant hospital 
records when patients are consented in order to confirm a previous full dilatation caesarean 
section occurred.  If these records are not available for review the patients will be excluded. 
Eligible women will be informed about the trial by a doctor, sonographer or midwife if their 
transvaginal ultrasound confirms a short cervix (25mm). Members of the research team 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 22 of 38 
C   RAFT 
(midwives, doctors and scanning practitioners) can then discuss the research further and consent 
women.  
 
• If a woman is randomised to a cervical cerclage, the procedure needs to take place within 
7 days of diagnosis of cervical shortening and removed around 37 weeks gestation. She 
will also have regular scan surveillance in accordance with local protocols. Rescue 
cerclage can be offered in cases of cervical opening with exposed membranes as per local 
guidelines. Targeted admission for bedrest and steroids can also be offered as per 
clinician practice and local protocols. 
 
• If a woman is randomised to the standard care arm; she will have regular surveillance 
scans and clinic visits in accordance with local protocols and clinician practice.  Rescue 
cerclage can be offered in cases of cervical opening with exposed membranes as per local 
guidelines. Targeted admission for bedrest and steroids can also be offered as per 
clinician experience and local protocols. 
 
Concomitant medication during RCT 
 
Participants are permitted to use any concomitant medication or treatment except progesterone 
alongside the trial management. This will be recorded at every visit on the RedCap database. Any 
other medication or treatment that would form normal clinical management for these women at 
risk of preterm labour i.e. antibiotics, corticosteroids, tocolytics etc. will be permitted according 
the local hospital guidelines and clinician preference. 
 
CRAFT-IMG 
 
Participants will be identified from CRAFT-OBS (30 women with history of FDCS and cervical 
length >25mm) and CRAFT-RCT (30 women with FDCS and short cervix (≤ 25mm) by their direct 
care team. Interested women will be directed to have more information from the research team 
as well as confirmation of informed consent. 15 women from CRAFT-RCT will have been 
randomised to cerclage and the other 15 to standard management. Only women recruited at St 
Thomas’ Hospital and UCLH will be eligible for this part of the CRAFT project. Doctors, 
sonographers or midwives in the research team will be recruiting patients to this sub-study. 
 
All MRI scans will be performed at St Thomas’ Hospital, and advanced protocol transvaginal 
ultrasound scans will be performed at both UCLH and St Thomas’ Hospital. Repeat imaging will 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 23 of 38 
C   RAFT 
be undertaken at regular intervals up to a maximum of 3 MRIs and 3 TVUS depending on patient 
availability in order to assess changes in the cervical tissue using the two imaging modalities. 
 
7.2. Consent procedure 
 
The study will be verbally explained to potential participants who will be given a written patient 
information sheet and adequate time for consideration and clarification of any queries. They can 
take the information home. For CRAFT-OBS and CRAFT-IMG, eligible patients will have until their 
next appointment to decide on participation and provide informed written consent. For CRAFT-
RCT, eligible patients will generally have up to 48 hours to decide on participation, depending on 
the length of their cervix and urgency of treatment as determined by the attending clinician.  
 
Written consent will be confirmed by an appropriately trained (GCP) clinician or researcher. 
Three copies of the consent form will be taken (1 for participant, 1 for clinical notes (unless 
electronic records), 1 for site file).  At the time of recruitment, a unique study number will be 
allocated to the patient. Only one copy of patient identifiable data linked to this number will be 
recorded on a password protected KCL computer in order that recruits can be contacted and 
delivery outcomes recorded. The research record will contain minimal identifiers such as initials 
and date of birth. Keeping initials and date of birth on the research database allows the data to 
be double-checked against source outcome data, therefore enhancing the reliability of the data.   
 
Consent will be sought to obtain NHS numbers for future tracking of outcomes. NHS numbers 
(mother and baby) will be collected to aid linkage to these future health records as well as follow 
up pregnancy and neonatal outcomes for recruits who move away from study sites. NHS numbers 
will be held separately from main study data and only linked with study ID. Access to this 
information will be limited to specific study staff. They will also be explicitly consented for use of 
the study data for future research, collection of additional data on any future pregnancies and 
whether they would be happy to be contacted about participation in further research studies 
that may be of interest to them.  
 
 
7.3. Data Collection 
 
Following consent, data on the participant’s demographic characteristics, risk factors, medical 
and obstetric history will be documented and entered onto the study specific database. This will 
include current and previous monitoring procedures and/or pregnancy interventions (e.g. 
cervical length measurements and cerclage). Cervical length will be measured with transvaginal 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 24 of 38 
C   RAFT 
ultrasound in accordance with local protocols, measurements will be taken in triplicate and the 
shortest measurement used.   Their pregnancy and neonatal outcomes will be collected from 
NHS patient records postnatally.   
 
Participants with a history of FDCS will be referred to a preterm surveillance clinic where they 
will be invited for cervical length assessment (with or without other tests, such as fetal 
fibronectin) from 14+0 to 23+6 weeks gestation. Cervical length will be measured with 
transvaginal ultrasound in accordance with local protocols, measurements will be taken in 
triplicate and the shortest measurement used.  If their cervical length is, or becomes 25mm 
during this period they will be offered the opportunity to participate in CRAFT-RCT.  Further 
explanation and a separate information sheet will be provided and additional consent form will 
be completed and stored as those for the main study.  If the participant is unwilling to participate 
in this randomised controlled trial she will continue to be monitored and cared for as per local 
protocol/clinicians’ experience, and continue in the observation arm of CRAFT study. Outcome 
data will be collected after the birth of her baby.  Women who provide written informed consent 
will be randomised to either cervical cerclage or standard care.     
 
Sixty participants, recruited at St Thomas’ and UCLH, will be invited to have additional imaging 
tests for the sub-study, CRAFT-IMG.  They will be given additional information and asked to sign 
another consent form, which will be stored as described above.   These additional tests will 
involve 
serial 
transvaginal 
ultrasound 
measurements 
of 
cervical 
length 
and 
macro/microstructural changes as per Prof Anna David’s protocol and MRI scans of 
macro/microstructural cervical change. 
 
Serial MRI scans will be performed on a 3-Tesla MRI scanner at St Thomas’ Hospital. Conventional 
imaging will include high resolution T1 and T2 weighted images as well as diffusion datasets. The 
first advanced protocol transvaginal ultrasound and MRI will occur at any time from 20 weeks 
gestation. Where delivery has not occurred, further imaging will be offered (up to a maximum of 
3 MRI and 3 of these transvaginal ultrasound scans). 
 
Outcome data: All participants’ data will be collated up until postnatal discharge. Neonates will 
be followed up until discharge or 28 days (whichever is sooner). Prompts on the database will 
alert the research midwife/assistant when each trial participant reaches her delivery date. Birth 
registers and in-patient records will be used to track hospital admissions and pregnancy 
outcomes. Outcome data (medical and economic) will be collected by review of NHS Maternity 
and medical records. If information is unavailable, e.g. if the delivery occurred elsewhere, the 
patient, patient’s GP or other hospital will be contacted. Gestational age will be calculated using 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 25 of 38 
C   RAFT 
ultrasound estimated date of delivery predicted at the 12-15 week ultrasound scan. The primary 
and secondary outcome data will be collected from hospital records after discharge from 
neonatal care. 
 
Source data and documents will be accessible by the research team only and any paper records 
will be stored in a locked cabinet in the Principal Investigators’ offices. Electronic versions of 
these source documents are stored on Trust computers only and behind the NHS firewall. The 
study may be subject to inspection and audit by King’s College London and Guy’s and St Thomas’ 
NHS Foundation Trust under their remit as sponsor and co-sponsor respectively, and other 
regulatory bodies to ensure adherence to GCP and the NHS Research Governance Framework for 
Health and Social Care. 
 
The identifiable information obtained as part of this study will be managed in accordance with 
the General Data Protection Act (2018). The computerised information is protected by a software 
and hardware barrier, and the records are handled in the same way as hospital records.  Data 
will be stored for 25 years in Trust firewalls/KCL Firewalls in accordance with legal requirements 
for the storage of maternity records. 
 
 
7.4. Trial intervention and additional imaging (CRAFT-RCT and CRAFT-IMG) 
 
At time of recruitment for CRAFT-RCT women will be randomly assigned (1:1) to cerclage or 
surveillance.  Randomisation will be carried out online via the RedCap web platform. Users will 
be assigned a personal identifier number.  Due to the nature of the interventions, the study is 
not blinded to the care providers or patient. Recruiters and trial co-ordinators will not have 
access to the randomisation sequence.  Women will be informed at time of recruitment to which 
arm they have been randomised.  A ‘minimisation’ procedure, using a computer-based algorithm, 
will be used to avoid chance imbalances in important stratification variables. Stratification 
variables will be a) gestation, b) BMI <30 or ≥30 kg/m2 c) risk factor (previous premature delivery 
<24 weeks, PPROM, late miscarriage or previous cervical surgery).  Women will not know what 
treatment they will be allocated prior to recruitment. RedCap will write the randomisation 
program and hold the allocation code. Contact information will be obtained from the patient.  
Demographic measures such as ethnicity, BMI etc will be entered into the central trial database.   
 
Following randomisation in CRAFT-RCT, the attending clinician will arrange for either a cervical 
cerclage (to be carried out within 7 days) or further observation as the randomisation indicates. 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 26 of 38 
C   RAFT 
There is no “emergency code break” procedure as the trial is open label randomised trial.  The 
method and materials used will be according to local protocols and clinician preference. 
 
Indications for withdrawal of treatment (removal of cerclage): 
 
• Participant request. 
• Elective preterm delivery. 
• Fetal membrane rupture. 
• Symptomatic placenta praevia. 
• Completion to 37 weeks gestation. 
 
 
Indication for additional treatment (rescue/emergency cerclage): 
 
• Exposed membranes or open cervix at 16+0-27+6 weeks gestation. 
 
The final study visit will take place between 34+0 and 37+0 weeks gestation. For those in the 
cervical cerclage arm an appointment for removal will be made for 37 weeks as per local policies 
and practice. If delivery occurs prior to this time the research team will collect this outcome data. 
Apart from the final study visit (34+0 and 37+0 weeks), all trial visits will occur during routine 
clinic attendances according to local clinical protocols and clinician practice.  
 
Participants of the imaging sub-study (CRAFT-IMG) will have a minimum of 1 advanced 
transvaginal ultrasound and 1 MRI up to a maximum of 3 MRIs and 3 advanced protocol 
transvaginal ultrasound scans (around 5 minutes longer than a cervical surveillance transvaginal 
ultrasound). The number carried out depends on the length of the pregnancy and patient’s 
availability.  Where possible these will be co-ordinated with clinical appointments to minimise 
disruption.  Participants will be offered reasonable reimbursement for their travel for these 
additional appointments. 
 
 
8. Data analysis 
CRAFT-OBS: This study will calculate prediction of preterm birth <37 weeks gestation in women 
with a previous CS in labour by observing clinical pregnancy outcomes.  Where data is available 
the predictive value based on cervical length and quantitative fetal fibronectin will also be 
assessed.  Results will be presented as both odds ratios and risk differences. Standard predictive 
statistics will be used for prediction of delivery <34 and <37 weeks gestation. 
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 27 of 38 
C   RAFT 
CRAFT-RCT: CRAFT-RCT: Statistical analysis of results will be undertaken by the research team 
and Mr Paul Seed.  The primary analyses will be by intention to treat. The main outcome is 
delivery under 34 weeks. Secondary analyses will include secondary endpoints as per section 4.2. 
Standard predictive statistics will be used for prediction of delivery <34 weeks gestation (cervix 
25mm will be calculated along with area under the curve). We will also validate our current 
predictive tools of cervical length and fetal fibronectin in this population.  Results will be 
presented as both odds ratios and risk differences, leading to number needed to treat (NNT) if 
appropriate, according to CONSORT guidelines. A subgroup analysis will be carried out according 
to other risk factors for preterm birth other than FDCS.  
 
 
CRAFT-IMG: This sub-study will provide data on relationships between macro/ micro-structural 
cervical defects in pregnant women who have had a previous FDCS and a short cervix 25mm, 
compared with those who have a cervix >25mm. Comparison will be made between the two 
groups.  Relative efficiency of detection of cervical defects by MRI (and relationships with 
outcomes), will be compared to those identified by ultrasound. We will also assess changes in 
the cervix over time.  This will be performed in conjunction with senior statistician Mr Seed.   
Images will be assessed for: overt structural abnormalities in collaboration with radiologists using 
a structured proforma. Patients and clinicians will be informed of clinically significant findings.  
These images will be compared to TVUS images in order to ascertain whether there is any 
correlation in findings between the two modalities (ref 910).  
 
Ultrasound data will be analysed contemporaneously at acquisition.  MRI data will be assessed 
for cervical anatomical features and presence and location of overt lesions or disruptions on 
conventional imaging (blinded to the participant’s history). Models will be fitted using the open-
source toolkits for diffusion data by Dr Hutter and Dr Paddy Slator (UCL)10,11, to obtain 
quantitative maps of tissue composition and microstructure properties. We will analyse the 
different imaging findings between short and long cervices and correlate it with their perinatal 
outcomes.  
 
9. Study Governance  
9.1. Ethics & Regulatory Approvals 
 
The study will comply with the principles of the Declaration of Helsinki and the principles of Good 
Clinical Practice (GCP) and in accordance with all applicable regulatory requirements including 
but not limited to the Research Governance Framework. This protocol and related documents 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 28 of 38 
C   RAFT 
will be submitted for review and receive approval from the Research Ethics Committee (REC).  
Additionally, local R and D approval will be sought in all participating centres.  Any future 
amendments, progress and final reports will be submitted as required. The study and any 
amendments will only be implemented following Ethics Committee and Trust approval by the 
R&D Department in each participating centre.  
9.2. Assessment of Efficacy for MRI and transvaginal ultrasound 
Image quality will be assessed by the research team.   
9.3. Procedures for Assessing Efficacy Parameters 
The within the research programme. Image quality is reviewed weekly and persisting issues 
analysed and appropriate action taken. This occasionally involves calling scanner engineers to fix 
a fault. 
 
9.4. Specification, Timing and Recording of Safety Parameters  
CRAFT-IMG: Each woman is assessed prior to MRI examination to ensure there are no 
contraindications to scanning. This includes a health check and a detailed metal safety check. 
Women are carefully placed inside the scanner to ensure comfort and safety. We are also in 
constant contact with the woman during the examination so if she is uncomfortable or feels 
unwell we can remedy the situation immediately. Full resuscitation equipment is always available 
outside the scanner and staff are trained in basic life support.  Any adverse events are recorded 
as for any Trust patient. 
 
9.5. Safety 
  
9.5.1 Assessment of Safety   
  
The Data Monitoring Committee (DMC) will be convened to ensure the wellbeing of study 
participants and the quality of the data collected (see below section 9.8).  The committee will 
periodically review study progress and outcomes as well as reports of serious adverse events 
(SAEs).  The DMC will, if appropriate, make recommendations regarding the continuance of the 
study or modification of the study protocol.    
  
9.5.2   Procedures for Recording and Reporting Adverse Events   
  
Serious adverse Event (SAE), Serious Adverse Reaction (SAR)   
  
The Medicines for Human Use (Clinical Trials) Regulations 2004 and Amended Regulations 2006 
gives the following definitions:  
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 29 of 38 
C   RAFT 
Adverse Event (AE): Any untoward medical occurrence in a subject to whom a medicinal product 
has been administered including occurrences which are not necessarily caused by or related to 
that product.  
 
Adverse Reaction (AR): Any untoward and unintended response in a subject to an investigational 
medicinal product which is related to any dose administered to that subject.  
Unexpected Adverse Reaction (UAR): An adverse reaction the nature and severity of which is not 
consistent with the information about the medicinal product in question set out in the 
Investigator's Brochure (IB) relating to the trial in question (for any other investigational product)  
 
Serious adverse Event (SAE) or Serious Adverse Reaction (SAR) is: 
 
Any adverse event, adverse reaction or unexpected adverse reaction, respectively, that  
- 
Results in death  
- 
Is life-threatening  
- 
Required hospitalisation or prolongation of existing hospitalisation, excluding admission 
for birth or unrelated pregnancy condition 
- 
Results in persistent or significant disability or incapacity  
- 
Is otherwise considered medically significant by the principal investigator.   
 
All AEs and SAEs must be recorded from the time a participant is randomized to treatment until 
30 days after stopping taking study drug and until pregnancy outcome (28 days after delivery). 
The Investigator should ask about the occurrence of AEs/SAEs at every visit during the study. 
Open-ended and non-leading verbal questioning of the participant should be used to enquire 
about AE/SAE occurrence. Participants should also be asked if they have been admitted to 
hospital, had any accidents, used any new medicines or changed concomitant medication 
regimens. If there is any doubt as to whether a clinical observation is an AE/SAE, the event should 
be recorded.  Hospitalisations for treatment planned prior to randomisation and hospitalisation 
for elective treatment of a pre-existing condition will not be considered as an SAE. Complications 
occurring during such hospitalisation will be AE/SAEs.  
  
Important Medical Events (IME): Events that may not be immediately life-threatening or result 
in death or hospitalisation but may jeopardise the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above should also be considered serious.    
  
9.5.3 Adverse events which do not require reporting  
  
Expected serious adverse events (SAEs) are those events which are expected in the patient 
population or as a result of the routine care/treatment of a patient.  The interventions they will 
be receiving are those which would be offered routinely in clinical practice. Cervical cerclage 
insertion is an established surgical procedure, which is associated with minimal risks. These 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 30 of 38 
C   RAFT 
include infection, miscarriage, bleeding, difficulty with suture removal and preterm prelabour 
rupture of membranes.  
  
Serious adverse events and serious adverse reactions (SARs) which are unrelated to these clinical 
procedures will be reported as SAEs.   
  
Events that are primary or secondary outcome measures are not considered to be SAEs and will 
be reported in the normal way, on the appropriate electronic case report form.  
  
Maternal:  
• 
Premature labour  
• 
Premature rupture of membranes  
• 
Chorioamnionitis  
  
Infant:  
• 
Perinatal death (unless unexpected at this gestation)  
• 
Low birth weight  
• 
Requirement for supplemental oxygen or ventilation support  
• 
Complications of prematurity (e.g. IVH, NEC, encephalopathy, seizures, hypoglycaemia) 
unless unexpected in this population  
• 
Admission of the baby to the neonatal unit  
  
In addition the following common pregnancy complication events will not be considered SAEs: 
hospitalisation for pre-eclampsia or pregnancy induced hypertension, hospitalisation for 
symptoms of preterm labour (e.g. rupture of membranes, vaginal bleeding); hospitalisation for 
maternal discomfort; hospitalisation for rest; hospitalisation for observation or monitoring for 
which the woman is admitted for a period of less than 12 h; delivery complications such as 
caesarean section or postpartum haemorrhage.   
  
9.5.4 Reporting Responsibilities   
  
All SAEs (excepting those specified in this protocol as not requiring reporting) will be reported 
immediately (and certainly no later than 24hrs) by the Investigator to the GSTT R&D Office and 
CI for review in accordance with the current Pharmacovigilance Policy. The Chief Investigator will 
report to the relevant ethics committee. Reporting timelines are as follows:  
 
The Chief Investigator (on behalf of the co-sponsors), will submit a Development Safety Update 
Report (DSUR) to the MHRA and REC annually.   
  
9.6. Trial Management Group 
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 31 of 38 
C   RAFT 
Study management meetings will be held approximately every two months (with video 
conferencing where required).  All researchers and clinicians affiliated with the project will be 
invited to participate in these meetings which will allow discussion of all aspects of the 
programme and the timely addressing of issues as they arise.  
 
9.7. Trial Steering Committee (TSC) 
 
The role of the Trial Steering Committee (TSC) is to provide the overall supervision of the study.  
The TSC will monitor the progress of the study and conduct and advise on its scientific credibility. 
The TSC will consider and act, as appropriate, upon the recommendations of the DMC and 
ultimately carries the responsibility for deciding whether the trial needs to be stopped on the 
grounds of safety or efficacy.  The TSC will consist of an independent chair and at least two other 
independent members (not involved in study recruitment and not employed by any organisation 
directly involved in study conduct.  A representative from our dedicated preterm birth studies 
Patient Public Involvement group will be invited to participate.  The first meeting will take place 
6 months after trial start date; frequency will be decided at the first meeting (at least annually). 
 
9.8. Data Monitoring Committee (DMC) 
 
A DMC independent of the applicants and TSC will review the progress of the trial at least 
annually and provide advice on the conduct of the trial to the TSC. The committee will periodically 
review study progress and outcomes. The timings and content of the DMC reviews will be 
detailed in a DMC charter which will be agreed at its first meeting. The DMC will meet 3 months 
following study commencement/recruitment of the first participant ; frequency of meeting will 
be decided at the first meeting. 
 
9.9. Study Coordinating Centre 
 
The trial coordinating centre will be the Department of Women and Children’s Health, Kings 
College London, where the study coordinator will be based.  The Division of Women’s Health will 
be responsible for statistical analysis, servicing both the DMC and the Trial Steering Committee 
(TSC) and, in collaboration with the Principal Investigators, study coordinator and Local Research 
Midwives/Nurses, for the day to day running of the study including recruitment of sites and 
training of staff.    
 
9.10. 
Trial stopping rules 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 32 of 38 
C   RAFT 
 
The CRAFT-RCT trial may be prematurely discontinued by the Sponsor, Chief Investigator or 
Regulatory Authority on the basis of new safety information or for other reasons given by the 
DMEC/TSC regulatory authority or ethics committee concerned. If the trial is prematurely 
discontinued, active participants will be informed and no further participant data will be 
collected. The Competent Authority and Research Ethics Committee will be informed within 15 
days of the early termination of the trial.  
 
10. Investigator responsibilities 
The Investigator is responsible for the overall conduct of the study at the site and compliance 
with the protocol and any protocol amendments. In accordance with the principles of GCP, the 
following areas listed in this section are also the responsibility of the Investigator. Responsibilities 
may be delegated to an appropriate member of study site staff. Delegated tasks must be 
documented on a Delegation Log and signed by all those named on the list.  
 
10.1. 
Data Handling 
All electronic data will be stored behind a secure firewall. Clinical information will be handled as 
appropriate for Trust patients to ensure maximum and efficient communication of results and 
clinical details to the appropriate clinical teams.  Any patient identifiable data transferred from 
behind the firewall will be anonymised prior to transfer. This will only be used with authorised 
collaborators with explicit knowledge of how the data is being used.   
 
The Principal Investigator is responsible for the quality of the data recorded in the electronic 
clinical research files.  The Chief Investigator will act as custodian for the trial data. Patient data 
will be anonymised. All anonymised data will be stored on a password protected computer.  All 
trial data will be stored in line with the Data Protection Act as defined in the Kings Health Partners 
Clinical Trials Office Archiving SOP.  
 
10.2. 
Data Sharing 
The Investigators will comply with the Kings College London (KCL) principles on data sharing and 
preservation.  The consent form states that other researchers may wish to access (anonymised) 
data in future. The trial co-ordinator and statistician will (in collaboration with the CI) manage 
access rights to the data set. Prospective new users must demonstrate compliance with legal, 
data protection and ethical guidelines before any data are released. 
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 33 of 38 
C   RAFT 
   
10.3. 
Linkage of data 
At the time of recruitment, a unique study number will be allocated to the patient. Only one copy 
of patent identifiable data linked to this number will be recorded on a password protected trust 
computer in order that recruits can be contacted and delivery outcomes recorded. The 
anonymised research record will not contain any patient identifiable data.  All records will be 
anonymised at time of data entry in accordance with the General Data Protection Act 2018. 
 
A bespoke internet-based data management system will be designed and built by RedCap and 
maintained by them.  Varying levels of access are available from simple user to global 
administrator, each level requiring individual log-in and password.  Minimal identifiers will be 
used on the main study database (initials, date of birth and unique study number). Contact details 
to ensure data completeness will be stored on a separate database linked only to study ID. 
 
Paper copies of consent forms will be stored numerically (by study ID) and kept in a locked filing 
cabinet in accordance to the General Data Protection Act 2018 and EU GDPR directive.  NHS 
numbers (mother and baby) will be collected to follow up pregnancy and neonatal outcomes for 
recruits who move away from study sites. NHS numbers will be held separately from main study 
data and only linked with study ID. Access to this information will be limited to specific study 
staff.      
 
10.4. 
GCP Training 
All study staff must hold valid GCP training certificates. This training will be updated every two 
years, or in accordance with local practice at collaborating sites, throughout the trial.  
 
10.5. 
NHS Trust Research and Development 
Individual sites will only start recruitment once they have received approval from their local NHS 
Trust Research and Development (R&D) offices. Applications to R&D offices will be submitted 
through the NIHR Co-ordinated System for gaining NHS permission. 
 
10.6. 
Protocol amendments 
Any changes in research activity, except those necessary to remove an apparent, immediate 
hazard to the participant, must be reviewed and approved by the Chief Investigator and the Co-
Sponsors notified. Substantial amendments to the protocol must be submitted in writing to the 
appropriate REC, Regulatory Authority and local R&D for approval prior to participants being 
enrolled into an amended protocol.  
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 34 of 38 
C   RAFT 
10.7. 
Protocol violations and deviations 
The Investigator should not implement any deviation from the protocol except where necessary 
to eliminate an immediate hazard to trial participants. In the event that an Investigator deviate 
deviation from the protocol, the nature of and reasons for the deviation should be recorded in 
the electronic clinical research files. If this necessitates a subsequent protocol amendment, this 
will be submitted to the REC, Regulatory Authority and local R&D for review and approval by the 
Chief Investigator.  
 
10.8. 
Direct access to source data and documents 
Meetings will be held on a regular basis by the research team to monitor and audit the conduct 
of the research and review aspects of the CRAFT’s study progress. The Investigator(s) will permit 
trial-related monitoring, audits, REC review, and regulatory inspections by providing the 
Sponsor(s), Regulators and REC direct access to source data and other documents (e.g. patients’ 
case sheets, MRI reports etc). 
 
 
11. Finance 
Funding to conduct the CRAFT trial and imaging substudy is provided by J.P. Moulton Charitable 
Foundation (grant reference no. 261294). The trial will be registered on the CRN portfolio (JRM 
is an NIHR partner organisation) and will be supported by NIHR CRNs (IRAS no. 261294/CPMS no. 
42833). 
 
12. Publication Policy 
Results of the study will be presented at national and international conferences and reported in 
peer reviewed journals.  No patient identifiable information will be published.  A lay summary 
will be available for participants via the study website. 
 
13. Insurance and Indemnity 
This study is co-sponsored by King’s College London and Guy’s and St Thomas NHS Foundation 
Trust. The sponsors will at all times maintain adequate insurance in relation to the study 
independently. King’s College London, through its own professional indemnity (Clinical Trials) and 
no-fault compensation and the Trust having a duty of care to patients via NHS indemnity cover, 
in respect of any claims arising as a result of clinical negligence by its employees, brought by or 
on behalf of a study patient. 
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 35 of 38 
C   RAFT 
 
14. Signatures 
 
 
______________________________________  
 
 
 
 
Chief Investigator                Date:  
 
 
 
 
 
 
 
 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 36 of 38 
C   RAFT 
REFERENCES 
 
1.  
UKPCN. Reducing Preterm Birth: Guidelines for commissioners and 
providers [Internet]. 2019 [cited 2019 Apr 4]. Available from: 
https://www.tommys.org/sites/default/files/Preterm birth guidelines.pdf 
2.  
England N. Saving Babies ’ Lives Version Two A care bundle for reducing 
perinatal [Internet]. 2019 [cited 2019 Apr 4]. p. 1–72. Available from: 
https://www.england.nhs.uk/wp-content/uploads/2019/03/Saving-Babies-
Lives-Care-Bundle-Version-Two-Final-Version2.pdf 
3.  
Levine LD, Sammel MD, Hirshberg A, Elovitz MA, Srinivas SK. Does stage of 
labor at time of cesarean delivery affect risk of subsequent preterm birth? 
Am J Obstet Gynecol [Internet]. 2015;212(3):360.e1-360.e7. Available from: 
http://dx.doi.org/10.1016/j.ajog.2014.09.035 
4.  
Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth 
from infancy to adulthood. Lancet. 2008;371(9608):261–9.  
5.  
Mangham LJ, Petrou S, Doyle LW, Draper ES, Marlow N. The Cost of Preterm 
Birth Throughout Childhood in England and Wales. Pediatrics. 
2009;123(2):e312–27.  
6.  
Iams JD, Goldenberg RL, Mercer BM, Moawad  a, Thom E, Meis PJ, et al. The 
Preterm Prediction Study: recurrence risk of spontaneous preterm birth. 
National Institute of Child Health and Human Development Maternal-Fetal 
Medicine Units Network. Am J Obstet Gynecol [Internet]. 1998;178(5):1035–
40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9609580 
7.  
Mercer BM, Goldenberg RL, Das A, Moawad AH, Iams JD, Meis PJ, et al. The 
preterm prediction study: a clinical risk assessment system. Am J Obstet 

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 37 of 38 
C   RAFT 
Gynecol. 1996 Jun;174(6):1885–93; discussion 1893-5.  
8.  
Tan, PS;Tan, JFH;Tan, EL; Tan L. Comparison of Caesarean sections and 
instrumental deliveries at full cervical dilatation: a retrospective review. 
Singapore Med J. 2018;  
9.  
Watson HA, Carter J, David AL, Seed PT, Shennan AH. Full dilation cesarean 
section: a risk factor for recurrent second-trimester loss and preterm birth. 
Acta Obstet Gynecol Scand. 2017;96(9):1100–5.  
10.  de Tejada BM, Faltin DL, Kinkel K, Guittier M-J, Boulvain M, Irion O. 
Magnetic resonance imaging of the cervix in women at high risk for preterm 
delivery. J Matern Neonatal Med. 2011 Nov;24(11):1392–7.  
11.  Masselli G, Perrone G, Kinkel K, Di Tola M, Laghi F, Gualdi G, et al. Are 
Second Trimester Apparent Diffusion Coefficient Values of the Short Uterine 
Cervix Associated with Impending Preterm Delivery? Radiology. 2016 
Sep;280(3):897–904.  
12.  Slator PJ, Hutter J, Palombo M, Jackson LH, Ho A, Panagiotaki E, et al. 
Combined Diffusion-Relaxometry MRI to Identify Dysfunction in the Human 
Placenta. Med Phys. 2018 Oct;  
13.  Le Bihan D, Breton E, Lallemand D, Aubin ML, Vignaud J, Laval-Jeantet M. 
Separation of diffusion and perfusion in intravoxel incoherent motion MR 
imaging. Radiology. 1988 Aug;168(2):497–505.  
14.  Lee EYP, Hui ESK, Chan KKL, Tse KY, Kwong WK, Chang TY, et al. Relationship 
between intravoxel incoherent motion diffusion-weighted MRI and dynamic 
contrast-enhanced MRI in tissue perfusion of cervical cancers. J Magn Reson 
Imaging. 2015 Aug;42(2):454–9.  

 
 
Study Protocol: Cerclage After Full-dilatation caesarean-secTion 
IRAS ID:261294 
REC: REC 19/LO/1270 
Version 2.0 
Date: 10.09.19 
 
Page 38 of 38 
C   RAFT 
15.  Van’t Hooft J, Duffy JMN, Daly M, Williamson PR, Meher S, Thom E, et al. A 
core outcome set for evaluation of interventions to prevent preterm birth. 
Obstet Gynecol. 2016;127(1):49–58.  
16.  Abbott DS, Radford SK, Seed PT, Tribe RM, Shennan AH. Evaluation of a 
quantitative fetal fibronectin test for spontaneous preterm birth in 
symptomatic women. Am J Obstet Gynecol [Internet]. 2013;208(2):122.e1-
122.e6. Available from: http://dx.doi.org/10.1016/j.ajog.2012.10.890