Mothers Working to Prevent Early Stillbirth Study 20-28
Conditions: Stillbirth and Fetal Death, Perinatal Death
Sponsor: University of Manchester

 
1 
 
 
 
 
 
 
FULL TITLE: Mothers Working to Prevent Early Stillbirth Study 
20-28 
 
 
 
SHORT STUDY TITLE: MiNESS 20-28 
 
PROTOCOL VERSION 1.4 
DATE 18/10/2023 
 
NCT06005272 
 
Amendment History 
Amendment 
No. 
Protocol Version 
and date  
Details of Changes Made 
NSA01 
1.2 01/08/23 
Correction of typographic errors in participant information 
sheets  
NSA02  
1.3 21/09/23 
Revision of inclusion/exclusion criteria and statistical analysis 
relating to control participants. Clarifies data sources to be 
accessed. 
NSA03 
1.4 18/10/23 
Change in process for providing record of consent to 
participant. Clarifies electronic storage of potentially 
identifying data will be within access-restricted folders  
 
RESEARCH REFERENCE NUMBERS  
● IRAS 314658 
● SPONSOR B01875  
● FUNDER NIHR204398 
● Clinicaltrials.gov NCT06005272 
 

 
 
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This protocol has regard for the HRA guidance and order of content 

 
 
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Signature Page 
The sponsor signature on the IRAS form, acts as documented acceptance that the sponsor approves 
the protocol. 
The Chief Investigator should sign below to confirm the following: 
The Chief Investigator confirms the protocol has been agreed and accepted and  agrees to conduct the 
study in compliance with the approved protocol and will adhere to the principles outlined in the 
Declaration of Helsinki, the sponsor’s SOPs, and other regulatory requirement. 
 I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the investigation without the prior written consent 
of the sponsor. 
I also confirm that I will make the findings of the study publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent account 
of the study will be given; and that any discrepancies from the study as planned in this protocol will be 
explained. 
 
Chief Investigator: 
Signature: ................... .................................... 
 
Date: 18/10/23 
Name: (please print): Dr Lucy Higgins  
 
 
 
 
 

 
 
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LIST OF CONTENTS 
 
GENERAL INFORMATION 
Page No. 
HRA PROTOCOL COMPLIANCE DECLARATION  
1 
TITLE PAGE  
1 
RESEARCH REFERENCE NUMBERS 
 
1 
SIGNATURE PAGE 
2 
LIST OF CONTENTS  
3 
KEY STUDY CONTACTS 
4 
STUDY SUMMARY 
6 
FUNDING 
 
7 
ROLE OF SPONSOR AND FUNDER 
7 
ROLES & RESPONSIBILITIES OF STUDY STEERING GROUPS AND INDIVIDUALS   
7 
STUDY FLOW CHART 
 
11 
SECTION  
1. BACKGROUND 
 
12 
2. RATIONALE 
 
14 
3. RESEARCH QUESTION/AIM(S)  
15 
4. STUDY DESIGN/METHODS 
17 
5. STUDY SETTING 
21 
6. SAMPLE AND RECRUITMENT 
22 
7. ETHICAL AND REGULATORY COMPLIANCE 
30 
8. DISSEMINATION  POLICY 
37 
9. REFERENCES 
39 
10. APPENDICES 
41 
 
 

 
 
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KEY STUDY CONTACTS 
Chief Investigator 
Dr Lucy Higgins  
Senior Clinical Lecturer / Honorary Consultant in 
Obstetrics 
Maternal and Fetal Health Research Centre  
University of Manchester  
5th Floor Research 
St. Mary’s Hospital  
Oxford Road 
Manchester  
M13 9WL  
Tel: 07739308508  
Email: lucy.higgins@manchester.ac.uk  
Fax: None 
Study Co-ordinator 
Lead Research Midwife for MiNESS 20-28 
Maternal and Fetal Health Research Centre  
University of Manchester  
5th Floor Research 
St. Mary’s Hospital  
Oxford Road 
Manchester  
M13 9WL  
Tel: 0161 701 6968 
Email: miness.20-28@mft.nhs.uk  
Fax: None 
Sponsor 
Dr Lynne Webster 
Director of Research Governance & Quality 
Research Office  
1st Floor Nowgen Building  
Grafton Street  
Manchester  
M13 9WU  
Tel: 0161 276 4125 
Email: Lynne.Webster@mft.nhs.uk 
Fax: None 
Funder 
National Institute for Health and Care Research  
Grange House 
15 Church Street  
Twickenham 
TW1 3NL  
Tel: 020 8843 8000 
Email: ccf@nihr.ac.uk 
Fax: None 
Key Protocol Contributors: 
Prof Alexander Heazell  
Dr Jack Wilkinson 

 
 
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Professor of Obstetrics  
Maternal and Fetal Health Research Centre  
University of Manchester  
5th Floor Research 
St. Mary’s Hospital  
Oxford Road 
Manchester  
M13 9WL  
Tel: 0161 276 6484  
Email: alexander.heazell@manchester.ac.uk  
Fax: None 
Lecturer in Biostatistics  
Centre for Biostatistics  
University of Manchester  
M13 9PL 
Tel: 0161 306 8008 
Email: jack.wilkinson@manchester.ac.uk 
Fax: None 
Committees 
Trial Management Group: 
Dr Lucy Higgins  
Senior Clinical Lecturer / Honorary Consultant in 
Obstetrics 
Maternal and Fetal Health Research Centre  
University of Manchester  
5th Floor Research 
St. Mary’s Hospital  
Oxford Road 
Manchester  
M13 9WL  
Tel: 07739308508  
Email: lucy.higgins@manchester.ac.uk  
Fax: None  
 
 
 
 

 
 
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STUDY SUMMARY 
Study Title 
Mothers Working to Prevent Early Stillbirth Study 20-28 
Internal ref. no. (or short title) 
MiNESS 20-28 
Study Design 
Observational case-control study 
Study Participants 
Cases: recently pregnant people who have experienced baby 
loss during pregnancy, labour or immediately after birth 
between 20-28 weeks of pregnancy  
Controls: individuals still pregnant/recently delivered at same 
gestational age  
Planned Size of Sample (if 
applicable) 
948 participants, of whom: 316 cases, 632 controls 
Follow up duration (if applicable) 
Until delivery (up to 24 weeks for control participants)  
Planned Recruitment Period 
1st September 2023 – 31st August 2025  
End of Study 
Collection of final pregnancy outcome data (up to 24 weeks/6 
months following recruitment of final participant).  
Planned Study End Date  
28th February 2026 
Research Question/Aim(s) 
 
Research question: Is early stillbirth associated with modifiable 
factors? 
 
Primary aim: to identify modifiable risk factors for early stillbirth 
that are amenable to public health campaigns or adaptation of 
antenatal care. 
 
Secondary aims: 
i. to confirm or refute whether the range of factors associated 
with late stillbirth are independently associated with early 
stillbirth, including (but not limited to) supine sleep position, 
caffeine intake and reduced fetal movement. 
ii. to 
explore 
interactions 
between 
maternal/parental 
characteristics (especially those relating to health 
inequalities 
including 
ethnicity 
and 
socioeconomic 
deprivation), fetal factors (including fetal growth restriction, 
reduced fetal movements) and early stillbirth risk. 

 
 
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iii. to determine whether exposures associated with early 
stillbirth vary by cause of death. 
 
 
 

 
 
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FUNDING AND SUPPORT IN KIND 
 
National Institute for Health and Care Research 
Research for Patient Benefit scheme: £259,093 
 
ROLE OF STUDY SPONSOR AND FUNDER 
Manchester University NHS Foundation Trust is acting as sponsor for this study and is assuming overall 
responsibility for the initiation and management of the study. The Trust will provide permission to 
conduct the research and monitor the progress of that research. The research team all hold substantive 
or honorary contracts with the Trust and therefore the sponsor has influence over all aspects of the 
study design, conduct, data analysis and interpretation, manuscript writing, and dissemination of results 
which are the responsibility of the research team. 
 
National Institute for Health and Care Research (NIHR) are the funder. The funder is not involved in the 
study design, conduct, data analysis and interpretation, or manuscript writing. The funder has 
undertaken peer review of the study proposal prior to funding award. 
 
Manchester University NHS Foundation Trust and the NIHR will undertake to assist dissemination of 
study results through highlighting the study findings on their communication channels.  
 
Final decisions relating to all aspects of the trial design, management and interpretation are the 
responsibility of the Chief Investigator. 
 
ROLES AND RESPONSIBILITIES OF STUDY MANAGEMENT COMMITEES/GROUPS & 
INDIVIDUALS 
Design of the study has been informed by consultation with members of the public with relevant lived 
experience relating to pregnancy and/or early stillbirth. A study-specific public-participant involvement 
(PPI) group was convened to aid development of the research question, terminology, research design 
and matters relating to widening participation in this research (see section 7.4). The main group will be 
reconvened at the end of the initial data analysis period to inform interpretation and public dissemination 
strategies.  
The Trial management group (TMG) comprises the study co-investigators, research midwife coordinator 
and sponsor representatives. It will be chaired by the Chief Investigator, meeting regularly at intervals 

 
 
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as determined by stage of study delivery (minimum six monthly) to review progress in study delivery 
and be collectively responsible for study management decisions.  
External scrutiny is welcomed. An advisory group, comprising two subgroups (a stakeholder advisory 
subgroup and an expert advisory subgroup), has been recruited. The stakeholder group, comprises 
representatives from key charities/community interest groups who represent the interests of potential 
research users (those with healthy pregnancies and those bereaved through baby loss at this stage of 
pregnancy), as well as public contributors representing the study-specific PPI group who have personal 
experience of pregnancy/antenatal care, with and without personal experience of bereavement at 20-
28 weeks’ gestation. The expert advisory group comprises international experts in stillbirth 
epidemiological research who have considerable experience in the design, delivery and analysis of 
similar stillbirth studies in other settings. They advisory group will advise the TMG, having particular 
input in the interpretation of the study findings and recommendations, the public and scientific 
dissemination plan and providing advice in the event of experiencing participant recruitment challenges.  

 
 
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PROTOCOL CONTRIBUTORS 
The protocol was drafted by Higgins and Heazell. All co-investigators have reviewed and approved the 
finalised version. Relevant sections of the protocol and associated documents have also been reviewed 
and edited by representatives of the study-specific PPI group. The study-specific PPI group members 
have informed of the study question, design, promotional materials and language used within the study 
documents. The Sponsor (Manchester University NHS Foundation Trust) has influence over all aspects 
of the study design, conduct, data analysis and interpretation, manuscript writing, and dissemination of 
results which are the responsibility of the research team. The Funder (National Institute for Health and 
care Research) has had no role in study design, nor will they have a role (beyond that described on 
page vii-viii) in study conduct, data analysis, interpretation, manuscript writing or dissemination of 
results. The Chief Investigator retains final decisions regarding any of these aspects of the study.  
 
KEY WORDS: 
Early stillbirth 
Perinatal death  
Case control study  
Risk factors  
Sleep position  
 
 
 

 
 
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Abbreviations 
 
Abbreviation 
Definition 
APR 
Annual progress report 
CI 
Chief Investigator 
Co-I 
Co-Investigator 
(e)CRF 
(electronic) Case report form  
DCC 
Direct clinical care  
GCP 
Good Clinical Practice 
IG 
Information governance  
IRAS 
Integrated research application system 
IT 
Informatics team 
HCRW 
Healthcare research Wales  
HRA 
Health research authority  
MBRRACE 
Mothers and babies: reducing risk through audits and 
confidential enquiries across the UK 
MFT 
Manchester University NHS Foundation Trust 
MiNESS 
Midlands and north of England stillbirth study  
MiNESS 20-28 
Mothers working to prevent early stillbirth study 20-28 
NHS 
National health service 
NICE 
National institute for health and care excellence  
NIHR 
National institute for health research  
PMRT 
Perinatal mortality review tool  
PPI 
Patient and Public Involvement 
PSP 
Priority setting partnership  
R&D 
Research and development  
REC 
Research Ethics Committee 
REDCap 
Research electronic data capture  
RFM 
Reduced fetal movement  
RM 
Research midwife 
Sands 
Stillbirth and neonatal death society  
SBL 
Saving babies lives  
SOP 
Standard operating procedure 
SMF 
Study management file 
TMG 
Trial management group  
UK 
United Kingdom  
USA 
United States of America 
 
 

 
 
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STUDY FLOW CHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: Study flow chart  

 
 
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STUDY PROTOCOL: MOTHERS WORKING TO PREVENT EARLY 
STILLBIRTH STUDY 20-28 (MiNESS 20-28) 
 
1 
BACKGROUND 
Stillbirth, the death of a baby before or during birth, is associated with adverse psychological, social and 
economic outcomes for the mother, their partner, their wider family and society (1). Stillbirth costs 
>£27.2M per year in the UK in healthcare, workplace absence and funeral costs alone (2). Reducing 
stillbirth and neonatal death is a Government priority (3) and a primary concern for parents and families 
(4, 5). To prevent these deaths it is important to understand modifiable risk factors for baby loss, a topic 
identified as a research priority by the Stillbirth and Miscarriage Priority Setting Partnerships (4, 5).  
In the UK, stillbirth (legally defined as death before birth of a baby ≥24 weeks’ gestation) affects 4 in 
every 1,000 UK births (over 2,500 cases each year). However, this number is an underestimate in the 
true burden of baby loss, as most high-income countries (e.g. USA, Australia) record stillbirths from 20 
or 22 weeks’ gestation. Studies demonstrate that baby death between 20 and 24 weeks’ gestation (an 
additional ~750 UK deaths/year) has a similar impact on parents’ physical and psychological wellbeing 
(6). There is also evidence that births with signs of life occurring at pre-viable gestations (between 20-
22 weeks’ gestation) are variously reported as stillbirths or neonatal deaths in different maternity units 
around the UK (7). Therefore, in line with parents’ requests and literature reviews, in this study we shall 
study baby deaths occurring between 20-28 weeks’ gestation, whether occurring before or during labour 
or immediately after birth. For consistency, these baby losses (legally second trimester miscarriage / 
stillbirth / immediate neonatal death) will be referred to as “early stillbirth”, in line with parents’ wishes 
(6).  
Previous and ongoing efforts to reduce stillbirth have principally focused on deaths occurring after 28 
weeks’ gestation. By understanding those at greatest risk of late stillbirth, effective healthcare 
interventions (e.g. Saving Babies Lives (SBL) Care Bundle V2 (8)) have been rolled out across England 
(and internationally). Consequently, UK stillbirths have reduced by 15% from 2014-2018 (9). The 
Midlands and North of England Stillbirth Study (MiNESS), the precursor of this current study, evaluated 
modifiable risk factors for stillbirth after 28 weeks' gestation, identifying an association with going to 
sleep on the woman’s back, among other potentially modifiable exposures (10, 11, 12, 13, 14). These 
findings informed national and international education campaigns and policy. As a result, sleep position 
recommendations for pregnant people have been incorporated into NHS England SBL Care Bundle V2 
(15) and NICE antenatal care guidelines (16). Dissemination of information about such modifiable 
factors in late pregnancy may be partly responsible for the recent reduction in late stillbirth in the UK 
and gives confidence in the ability of this study to produce a further reduction by doing the same for 
early stillbirth. Critically, there has been no reduction in the number of stillbirths occurring before 28 

 
 
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weeks – which account for 40% of losses (~1,600 losses between 20-28 weeks each year). In order to 
meet the UK Government’s target of 50% fewer stillbirths by 2025 (and beyond), early stillbirths 
occurring before 28 weeks of pregnancy must also be reduced. 
1.1 Trial design: 
This 
is 
a 
non-interventional 
(observational) 
questionnaire-based 
case-control 
study. 
316 
mothers/parents who have recently been bereaved through early stillbirth at 20-28 weeks’ gestation 
(before/during labour or immediately after birth), and 632 people who were still pregnant at the same 
gestation will complete one interview with a research midwife. The interview will take the format of a 
research midwife-administered (and completed) questionnaire which gathers information about the 
background, exposures and healthcare of the individual in pregnancy, in particular during the weeks 
immediately before the gestation at baby loss/interview. Supplementary information will be collected 
from the medical records relating to the pregnancy/birth.  
1.2. Review of existing evidence: 
Approximately 2 in every 1,000 pregnancies in the UK will end in early stillbirth at 20-28 weeks’ gestation 
(~1,600 losses each year). A cohort study of the causes of early stillbirth in Australia (2013-2018) found 
~10% were due to congenital anomalies, 30% due to preterm labour or antepartum haemorrhage, 20% 
were unexplained and the remainder were attributed to a variety of perinatal conditions (17). National 
MBRRACE-UK data for stillbirths at 22-28 weeks’ gestation (co-applicant Smith, personal 
communication) shows similar patterns; 6% were attributed to congenital anomalies, 33% to placental 
conditions and 28% to unknown causes. To date, efforts to prevent early stillbirth are limited by a 
significant proportion of losses having no clear identified cause. Better understanding of early stillbirth 
causes can be used to ensure that appropriate preventative healthcare services are provided. However, 
there is an evidence gap relating to what factors are associated with increased or decreased risk of 
early stillbirth. 
One example of the gap in information is caffeine consumption. A systematic review of 14 observational 
studies suggested caffeine consumption ≥300-350mg/day in pregnancy was associated with increased 
risk of pregnancy loss and late stillbirth (13, 18). However, only two studies included early stillbirth, 
meaning there are insufficient data on which to base education programmes aiming to assist individuals 
to modify caffeine intake in pregnancy. A lack of information on risk factors may also lead to 
inappropriate maternity service attendances. For example, the association between reduced fetal 
movements (RFM) and stillbirth after 28 weeks’ gestation has been recurrently described (12, 19). 
However, 20% of women presenting with RFM do so prior to 28 weeks’ gestation at a time when many 
pregnancies have not yet established a regular pattern of movement (20). Thus, extrapolating data from 
studies conducted later in pregnancy may lead to either over- or under-investigation (and intervention) 

 
 
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for this, and similar, common presenting complaints and may increase perceived stress in relation to 
this. Furthermore, six observational studies have demonstrated an association between going-to-sleep 
position (and other sleep habits) and risk of stillbirth after 28 weeks' gestation (21). However, the impact 
of supine going-to-sleep position on early stillbirths is unknown. Although the NuMom2b cohort study 
from the USA suggested no relationship with stillbirth, this analysis was underpowered (24 stillbirths / 
8,706 participants) (22); a relationship to early stillbirth remains biologically plausible because uterine 
blood flow reduces in a supine position from 20 weeks' gestation onwards (23). Therefore, determining 
the relationship between modifiable factors and early stillbirth is important to enable public education 
campaigns or adaptations to maternity care to be targeted at the correct stage of pregnancy. 
 
2 
RATIONALE  
Our research user engagement activities, and two relevant priority setting partnerships (4, 5) involving 
more than 1,000 individuals identifying as parents, family members or individuals with miscarriage 
experience highlights that pregnant people are highly motivated to improve their baby’s health in 
pregnancy, and that understanding and addressing modifiable risk factors for baby loss is a key research 
priority for them. However, there is an evidence gap related to modifiable risk factors for early stillbirth. 
Consequently, expectant parents report an information void in relation to prevention advice and public 
awareness of early stillbirth is low.  
Early stillbirths are likely to have different causes to those after 28 weeks’ gestation. For example they 
may involve preterm birth processes or extreme early onset fetal growth restriction. Further, maternal 
and fetal physiology is different at this earlier stage of pregnancy with many babies not yet having an 
established fetal movement pattern, and less impact of supine sleep position on uterine blood flow. It is 
therefore likely that previously identified modifiable risk factors for late stillbirth (such as sleep position 
or fetal movement changes) may not impact on early stillbirth risk in the same way. It is also likely that 
there are novel additional factors specific to early stillbirth. This study will address the need for 
information on risk factors for early stillbirth, specifically identifying modifiable factors independently 
associated with baby loss occurring between 20 and 28 weeks of pregnancy. These factors may include 
'exposure' factors (e.g. diet, sleep characteristics, physical activity), health inequalities (ethnicity, 
deprivation or exposure to domestic violence) and healthcare factors (e.g. timing and content of lifestyle 
advice, antenatal screening/care provided, management of extreme preterm labour).  
Information about modifiable factors associated with early stillbirth is now urgently required to inform 
clinical practice, to assist expectant mothers/parents to reduce their baby’s risk of stillbirth, and to help 
address inequalities in pregnancy outcome. This study will focus on what portion of early stillbirth risk 
may be mitigated by facilitating positive health exposures among expectant mothers/parents and their 
partners, or by adaptation of their environment or healthcare provision. Information obtained from this 

 
 
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study will enable antenatal care and education to be developed to reduce the risk of these earlier 
stillbirths. 
 
3 
RESEARCH QUESTION/AIM(S) 
This study addresses the research question “Is early stillbirth associated with modifiable factors?” It 
specifically aims to: 
1.  Identify modifiable risk factors for early stillbirth that are amenable to public health campaigns or 
adaptation of antenatal care. 
2.  Confirm or refute whether the range of factors associated with late stillbirth are independently 
associated with early stillbirth, including (but not limited to) supine sleep position, caffeine intake 
and reduced fetal movement. 
3.  Explore interactions between maternal/parental characteristics (especially those relating to 
health inequalities including ethnicity and socioeconomic deprivation), fetal factors (including 
fetal growth restriction, reduced fetal movements) and early stillbirth risk. 
4.  Determine whether exposures associated with early stillbirth vary by cause of death. 
 
3.1 
Objectives 
The study’s principal objectives are: 
1. 
To conduct structured interviews with bereaved mothers/parents or pregnant people to gain a 
deeper understanding of potentially modifiable risk factors which affect their baby’s risk of early 
stillbirth  
2. 
To describe associations of potentially modifiable risk factors for early stillbirth according to 
different causes of early stillbirth  
The secondary objectives are to: 
1. 
Confirm or refute whether factors associated with late stillbirth are independently associated with 
early stillbirth. 
2. 
Explore interactions between maternal characteristics (especially those relating to health 
inequalities including ethnicity and socioeconomic deprivation), fetal factors (including fetal 
growth restriction, reduced fetal movements) and early stillbirth risk. 
3. 
Determine whether exposures associated with early stillbirth vary by cause of death. 
3.2 
Outcome 
The primary output from this research will be identification of novel modifiable risk factors for baby loss 
occurring during pregnancy/birth or immediately after birth between 20-28 weeks’ gestation (collectively 
termed early stillbirth according to parental request). Specifically, this study will confirm or refute whether 

 
 
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risk factors for late stillbirth described above are relevant for early stillbirth. This will ensure evidence-
based information for pregnant people, and those caring for them, to take positive steps to improve the 
health of their baby in the second trimester.  
This approach extends the successful model used for the first MiNESS study to achieve similar 
breakthroughs in early stillbirth. Our findings will have direct impact on policy and practice through future 
iterations of the NHS SBL Care Bundle for dissemination by our stakeholder organisations. Assuming 
that a similar population attributable risk for early stillbirth to that seen in later stillbirths is attributable to 
identifiable modifiable factors, we would anticipate a 20% reduction in early stillbirth within five years 
(~320 fewer deaths/year). Our track record of translating research findings into national clinical policy 
indicates that our study findings would be clinically relevant and rapidly translated into parent information 
campaigns and national clinical guidance. 
Secondary benefits would include an increased awareness of early stillbirth, a greater understanding of 
the factors that impact on inequalities in outcome, improved understanding of the causes of early 
stillbirth and potential reductions in the rate or severity of related pregnancy complications (e.g. 
preeclampsia and preterm birth) by early identification of pregnant people at risk, facilitation of lifestyle 
modification and improving access to evidence-based preventative healthcare. Reduction in these 
related pregnancy complications will realise cost savings (e.g. £9,000 excess healthcare costs per case 
of preeclampsia (24)). Population-based interventions to prevent early stillbirth are likely to 
simultaneously convey wider-reaching healthcare and economic benefits for pregnancy care. Our 
research user engagement activities indicate that giving bereaved mothers/parents the opportunity to 
talk about their baby, and their baby’s life and birth, and by sharing those messages with healthcare 
professionals and other (future) parents, will assist in breaking down taboos surrounding (early) stillbirth 
and raise awareness of early stillbirth/early stillbirth prevention among pregnant people of the future and 
their family/friend support systems.  
 
4 
STUDY DESIGN AND METHODS OF DATA COLLECTION AND DATA ANALYSIS 
4.1 Study design 
The researchers will conduct a prospective case-control study of people who experience early stillbirth 
and those who have a contemporaneous ongoing pregnancy using approaches successfully employed 
in the original MiNESS (25). A schedule of events is found in Appendix 1. A case-control study is the 
most appropriate, efficient, design to study relatively rare disorders such as early stillbirth. This design 
also has the advantage of being able to study multiple exposures in the same study. Alternative study 
designs have been carefully considered but not pursued. Routine data studies lack detailed information 
regarding pregnancy exposures (e.g. sleep practices, caffeine consumption), while cohort studies of 

 
 
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pregnant people would be unaffordable and impractical as they would require >158,000 participants, 
assuming an early stillbirth rate of 2/1,000 pregnancies, in order to include sufficient cases (N=316) in 
which to detect clinically important exposures associated with early stillbirth. 
This method also overcomes limitations of previous studies using gestation-matched live birth cohorts 
(which includes many infants who have risk factors for preterm birth). The study will exclude fetuses 
with serious congenital abnormalities, as these deaths are not amenable to prevention by interventions 
during pregnancy. While participating units will be welcomed from around the United Kingdom, it is 
anticipated that the majority of all participating units/participants will be within England, with a particular 
focus on units in the Midlands and North of England. This is because there is a network of maternity 
units established from the original MiNESS study and this area has maternity units serving a socially 
and economically diverse population. Traditionally, the Midlands and North of England has a stillbirth 
rate above the national average highlighting the need for improvements in this area.  
 
The study will end upon collection of the final pregnancy outcome data for all enrolled participants. As 
control participants may participate as early as 20 weeks’ gestation and may not deliver until 42 (or 
more) weeks of pregnancy, and/or bereaved participants’ postmortem investigations may take (on 
average) 12 weeks to be reported, final study data collection may take up to six months following 
recruitment of the final participant. 
4.2 Methods of data collection 
Participants will be interviewed via Microsoft Teams or face to face (by mutual agreement) by trained 
research midwives, with an interpreter where required. Where interviews occur face to face these will 
be conducted in a suitably private location. For bereaved mothers/parents (cases), this will occur, where 
possible, within three weeks of loss (maximum six weeks) and people with ongoing pregnancies at the 
same gestation (controls) will be interviewed within the same time period of the target gestation 
(informed by that of historic losses in that unit according to the Standard operating procedure (SOP) for 
identification and approach of potential control participants).  
Interviews will not be recorded. However, the process of obtaining verbal consent will be recorded 
according to the SOP for Documenting Virtual Consent. Standardised interviews, using an online study 
questionnaire administered and completed by research midwives, will be used to improve reliability of 
self-report measures and will stress the importance of giving honest answers, but also the option to 
decline to answer any question. Confidentiality will be emphasised, and interviews will be conducted by 
experienced interviewers who are not the caregiver (26),and have been trained by the coordinating 
midwife based in Manchester/co-investigator team in structured interview format and appropriate 
environment provision, from whom they will receive ongoing support. 

 
 
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The research midwife-administered study questionnaire used during the standardised interview will 
collect data on: 
● Social and demographic characteristics of the participant and those of any partner including age, 
ethnicity, educational attainment, income, postcode (to allow calculation of deprivation indices), 
preferred language, immigration status and length of residence in the UK. 
● Past obstetric history, including use of fertility treatment. 
● Past medical history and medication/supplement use. 
● Lifestyle determinants such as use of cigarettes, alcohol and street drugs prior to conception 
and during pregnancy. Information on caffeine consumption is included as this was associated 
with late stillbirth in MiNESS but lacks an evidence base in relation to early stillbirth. 
● Exposure to stress and violence. The perceived social stress scale is used to obtain data on 
social stress experienced by participants (27), the multidimensional scale of perceived social 
support is used to obtain data on participants’ support networks (28) and the presence of intimate 
partner violence is assessed by standardised questions. 
● Sleep behaviour and perception of fetal movements. 
 
Additional data will be collected from the participant’s medical records for the current pregnancy 
including:  
● Results from blood tests and ultrasound scans. 
● Healthcare episodes in pregnancy 
● Blood pressure and body mass index 
● Baby’s’ birthweight 
Separate medical records belonging to the infant will not be accessed. 
 
Pilot interviews indicate that the majority of questionnaires will take 1-1.5 hours to complete (plus 5-10 
minutes to record verbal consent). Interviews may take longer, particularly for bereaved individuals, 
where the participant may have more detail to communicate to the researcher; research midwives 
administering the questionnaires are encouraged to facilitate this where possible. 
 
Where an individual participates in the study twice in the same pregnancy (once as a control and once 
as a case), a separate interview will be conducted for each participation as the range of questions asked 
differs depending on case/control status, and exposures (such as sleep position etc) may differ between 
control interview and subsequent early stillbirth. Research Midwives should discuss with the participant 
that answers from the previous interview can be re-used in order to prevent participants having to repeat 
themselves, where they do not change over time (for example background sociodemographic data). 

 
 
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However, where exposures may have changed over time (such as sleep position, substance exposures 
etc) these questions will be asked again. Data from the first interview (as a control) will be retained 
unless a specific request to withdraw data is received.  
4.3 Standard care anticipated for participants 
Participants (bereaved or those with ongoing pregnancies) will continue to be cared for by the health 
professional(s) responsible for their care. In the event of a participant (bereaved/otherwise) becoming 
upset/distressed by the questions asked the research midwife should follow the study distress protocol 
and give the option to pause or stop the interview, discuss local pathways to continuing care/counselling 
and offer referral to local support agencies. In the unlikely situation where an individual is identified as 
being a risk to themselves or an identifiable other, standard safeguarding practices (per local hospital 
policies) will be followed, obtaining consent to information sharing/disclosure where possible from the 
participant.  
4.4 Data Management  
The data sources for assessing eligibility of potential participants, and the sociodemographic 
background, exposures to potentially modifiable risk factors for early stillbirth and occurrence of the 
outcomes of interest (early stillbirth and broad category of stillbirth cause) are as follows: 
I. 
Participant verbal responses during structured interview 
II. 
Participant medical records including 
• 
Paper or electronic documentation of healthcare encounters  
• 
Paper or electronic reports from laboratory, radiology, and point of care investigations  
III. 
Perinatal mortality review tool (PMRT)  
Data will be entered directly onto an electronic case report form (eCRF; there will be no paper CRFs) 
and collated using a secure online database (REDCap). REDCap is a secure web application for building 
and managing online surveys and databases. In this study, it is being used to host online 
CRF/questionnaires. The system is specifically designed for research and data is stored on an MFT 
server (not shared with any third party). MFT servers are backed up at the end of each day and are 
maintained by MFT Informatics Team (IT). If data is lost, it can be recovered via the Trust IT back up 
service for the REDCap server. The Data Report can be downloaded from REDCap in the form of an 
Excel spreadsheet, this will be saved under a study folder with permissions based as to who can amend 
and view the data within the study team. The Data Report from REDCap will include participants’ 
postcodes, dates of birth and medical history and is classed as identifiable. These will be stored, on a 

 
 
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Trust encrypted password protected device at MFT in keeping with the Information Governance (IG) 
arrangements. 
In this database and data report participants will be allocated, and identified by, a unique study 
identification number. A separate log linking the unique study identification number to the participants’ 
identifiable data (name, date of birth, hospital number) will be maintained securely at each participating 
hospital. During study recruitment/follow up this will be an electronic file, stored on the local NHS Trust 
server; a site file note will be made documenting where this file is stored. After the end of the study it 
will be printed, stored in the site file and the electronic copy deleted, being stored locally for a minimum 
of five years (longer if required according to sponsor SOPs/guidance at the time). After data collection 
is complete, the central research team will download all pseudonymised study data into a Microsoft 
Excel file and this will be stored securely on the MFT server. The central research team/Sponsor will 
not be able to identify participants from the data submitted centrally. This data will be processed to check 
for internal consistency (e.g. to ensure that the entered dates/gestations of certain antenatal events 
were not after the reported date/gestation of delivery/interview; data queries against potential data entry 
errors will be raised and resolved) and to derive variables from potentially identifying variables (such as 
indices of multiple deprivation or air pollution indices from postcode data and age from date of 
birth/delivery data) before they are removed to generate a fully anonymised dataset which will be saved 
as a .csv file to a restricted access area of the MFT server and stored for 5 years following completion 
of the project, or in line with MFT policies and in accordance with International conference on 
harmonisation of technical requirements for registration of pharmaceuticals for human use Good Clinical 
Practice (GCP). Fully anonymised data may be made available to other researchers either through a 
central research data repository, or via request from other researchers, after publication of the initial 
study findings. Refer to the data management plan for further details. 
4.4.1  Consent to future contact  
During the process of obtaining participant consent, participants will be asked to indicate whether they 
are willing for the researchers to contact them in two circumstances: i) to receive a summary of the study 
findings, and ii) in the case of relevant future follow-on studies relevant to their pregnancy/birth. If 
permission is given, this will be recorded in the study recruitment log and contact details retained for 
these purpose(s). If consent for future research invitations is granted there will be a maximum of three 
invitations per participant to future research opportunities related to early stillbirth over the following five 
years (renewable for a further five year period if the participant wishes, as part of one of these contacts). 
There will be no obligation to take part in any future research study. Participants can request not to be 
contacted again in which case the research team will delete all details held.  

 
 
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4.5 Statistical analysis 
Unadjusted associations between the outcome (early stillbirth) and each exposure will be estimated. 
Logistic regressions, adjusted for confounding variables, will consider multiple exposures in relation to 
early stillbirth. A separate logistic model, including a set of confounding variables (elucidated using 
causal diagrams (30)), will be used for each exposure variable to avoid spurious inferences (31). All 
models will include age, first pregnancy, self-declared ethnic group, smoking, obesity, diabetes, and 
hypertension. Both unadjusted and adjusted estimates and 95% confidence intervals will be presented 
for all exposure variables. Likelihood Ratio Testing will be used to test for an effect of each exposure. 
All analyses will be conducted for all cases; secondary analyses will be conducted by early stillbirth 
subtype (preterm delivery, unexplained in utero, explainable in utero) and repeated including only babies 
without any sign of life after birth. Missing data will be assessed, incorporated, and reported in line with 
recent guidance from the Strengthening Analytical Thinking for Observational Studies (STRATOS) 
Initiative (32). Participants who withdraw from the study after participation will not be replaced; data 
already collected will continue to be used, in line with the participant information sheet, unless a specific 
request to delete data is received before the data enters the public domain through publication and 
deposition in a central research repository. Where an individual participates as both a control and case 
participant, each collected dataset will be used independently, with appropriate adjustment made for 
repeat participation. Analyses will be conducted in Stata, R or other appropriate statistical analysis 
software. Study data will be compared with national data (MBRRACE UK; via co-applicant Smith) to 
assess generalisability (9). 
 
5 
STUDY SETTING 
This is a multicentre study taking place in maternity units in the United Kingdom. The majority of research 
sites will be in England, but participating sites are welcomed from Northern Ireland, Scotland and Wales. 
In accordance with the recommendations of the study-specific PPI group, most data collection will occur 
by remote video call. Microsoft Teams is the sponsor-preferred video calling software and preferred 
format for study interviews. Some interviews may take place face to face, according to participant 
preference. Translators will be provided where necessary. Data extraction from source data, namely the 
(recently) pregnant individual’s medical records pertaining to the pregnancy including medical 
investigations in pregnancy/around the time of birth, and PMRT (bereaved parents only) will occur at 
participating maternity units.  
All individuals receiving antenatal care in participating maternity units will be made aware of the study 
through provision/display of promotional materials designed with the input of the study-specific PPI 
group; study awareness posters will be displayed in antenatal clinic and ultrasound department waiting 
areas and a study awareness leaflet will be provided at 16 week antenatal appointments to all pregnant 

 
 
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people with singleton pregnancies in participating maternity units. Self-referrals to the study are not 
accepted in order to limit sampling bias. Bereaved mothers/parents (cases) will be approached prior to 
discharge from the maternity unit by their midwife, bereavement midwife or doctor, and consent obtained 
to refer the individual to the study team and allow contact by a research midwife. Pregnant people 
(controls) will be randomly identified by the local research team from participating maternity units’ 
booking lists according to the process described in section 6.2.2 and using the selection system 
described in the SOP for identification and approach of potential control participants, and will be 
approached in-person by a member of the research team at an appropriately timed routine antenatal 
appointment (usually the routine fetal anomaly scan). This methodology was successfully employed in 
the previous MiNESS study, and research user engagement indicates that this approach is favoured 
over other options.  
 
6 
SAMPLE AND RECRUITMENT 
6.1  
Eligibility Criteria 
All individuals will be considered for inclusion in this study regardless of age, disability, gender 
reassignment, marriage and civil partnership, pregnancy and maternity, race, religion and belief, sex, and 
sexual orientation except where the study inclusion and exclusion criteria explicitly state otherwise. Current 
or recent pregnancy/maternity is a required characteristic for inclusion due to the nature of the study 
question. 
 
6.1.1 Inclusion criteria  
Overall inclusion criteria:  
[1] People receiving pregnancy care and/or giving birth in a participating maternity unit during 
the study period 
[2] Singleton pregnancy/birth  
[3] Baby without (evident) serious congenital abnormality* 
[4] Between 20-28 weeks of pregnancy$  
 
Specific inclusion criteria relevant to study group: 
Cases participants only:  
[A] Where baby was diagnosed to have died before/during or immediately after labour  
[B] Where baby diagnosed to have died between 20-28 weeks of pregnancy 
 
Control participants only:  

 
 
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[C] Ongoing pregnancy at the target gestation (as specified by the control identification tool 
between 20 to 28 weeks of pregnancy), even if no longer pregnant at the time of interview. 
 
Where a control participant subsequently experiences early stillbirth after participating in the study, a 
sensitive re-approach to participate a second time as a case participant may be made, if deemed 
appropriate by the direct care team. There will be no obligation to participate a second time.  
6.1.2 Exclusion criteria  
All participants: 
i. Presence of a known significant congenital anomaly (as informed by the NHS Fetal Anomaly 
Screening Programme (33)) 
Participants who give birth to liveborn baby with a significant congenital anomaly after 
participation will be excluded from data analysis 
ii. Multifetal pregnancy 
iii. Inability to give consent despite provision of translation services as required 
iv. Participant age <16 years 
v. Individuals not receiving care through a participating hospital 
 
Case participants only  
I. 
vi. Where signs of life were DETECTED after birth, attempted transfer of the infant to neonatal 
services 
Resuscitation attempts are NOT an exclusion if NO ATTEMPT TO TRANSFER TO NEONATAL 
SERVICES was made. 
 
 
6.2  
Sampling 
Cases: All bereaved mothers/parents meeting study inclusion criteria delivering in participating 
maternity units within the study recruitment period will be approached to participate. It is anticipated 
from previous research (11, 34, 35) that 50-75% of bereaved individuals approached will agree to 
participate. 
Controls: Pregnant people with ongoing pregnancies, who meet the study inclusion criteria, will be 
recruited in a 2:1 ratio to the expected number of bereaved participants in that unit. It is anticipated that 
between 2-3 pregnant individuals will need to be approached to recruit one control participant (11, 34, 
35).  

 
 
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6.2.1  Size of sample 
Early stillbirth occurs in ~0.3% of births (22). Recruiting 316 cases and 632 controls (two controls per 
case) will detect associations with an odds ratio of 1.5 or greater (i.e. an associated fetal death rate of 
0.45% or more) with 80% power and 5% significance level, where 30-60% of participants are exposed. 
Individual early stillbirth subtypes (preterm delivery, unexplained in utero, explainable in utero) are 
expected to occur in a 1:1:1 ratio. If these are differentially affected by certain exposures, the sample 
size is adequate to detect subtype-specific associations with an odds ratio of 2 or greater (same power 
and significance level, assuming 30-60% exposure). Larger effect sizes are expected in relation to 
subtype-specific risk factors compared to overall analyses, as subgroup effects will be attenuated by 
patient heterogeneity in the latter.  
A 37% overall participation rate was observed in MiNESS (49% among bereaved mothers/parents) (11). 
Assuming similar rates of recruitment are achieved in the proposed study, we will need to approach 644 
bereaved mothers/parents and 1,915 pregnant people to achieve the desired sample size. With ~1,450 
UK early stillbirths without congenital anomalies per year, by recruiting in multiple locations we believe 
this recruitment target can be achieved within 24 months. However, we have adopted a series of 
approaches to improve participation rates from our experience of running the original MiNESS study, 
and from working with our study-specific PPI group. These approaches, including involvement of 
bereavement/usual care teams in the initial approach to bereaved/pregnant participants, raising 
awareness of the study among the general pregnancy population in advance of approach and provision 
of the option for online interviews including with translation facilities are expected to improve recruitment 
rates. In the Auckland Stillbirth Study, co-applicant Stacey achieved a 72% participation rate (35); this 
expertise will inform research midwife training in relation to study approach. The TMG will review 
recruitment rates quarterly; if a minimum recruitment rate of 50% is not achieved in each group at each 
site, we will examine patterns in recruitment data, investigate local/national barriers to recruitment and 
seek input of the SSG to overcome these. Thus, we are confident that a higher ratio of recruits to 
individuals approached will be achieved in the current study.  
6.2.2  Sampling technique 
Cases: All bereaved mothers/parents meeting study inclusion criteria delivering in participating 
maternity units within the study recruitment period will be approached to participate (total population 
sampling).  
Controls: Self-referral to the study is not accepted. Individuals will be randomly selected from up to date 
(refreshed every 4-8 weeks) booking lists at participating hospitals by appropriate members of the local 
study team, adhering to the highest standards of research practice. Details of the sampling technique 
to be employed for control participants is provided in SOP for identification and approach of potential 
control participants; a bespoke control participant identification spreadsheet will be provided for each 

 
 
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site based on the gestation distribution of individuals delivering locally within the last three years who 
would have met the study “case” inclusion criteria, and birth rate at that unit. This identification algorithm 
will be applied by the local study team to each participating maternity unit’s own booking list, so that all 
eligible pregnant individuals receiving care in participating hospitals have an equal chance of being 
approached. This will attempt to ensure that the “control” participants of the study are well-matched to 
the “case” participants in terms of key non-modifiable risk factors for early stillbirth. Should an individual 
approached to participate as a “control” participant decline participation, the selection SOP will be re-
performed and the next individual will be approached, and so on, until a control participant of that 
demographic is recruited. This approach was successfully adopted in the original MiNESS study. 
6.3 
 Recruitment 
Recruitment is outlined in Figure 1 (flow chart). On the advice of the study-specific PPI group, all 
pregnant people receiving antenatal care at participating hospitals will be made aware of the ongoing 
study, its purpose, and that they may be invited to participate prior to any recruitment approach being 
made. This information will take the form of study awareness posters displayed in hospital/community 
antenatal clinic and ultrasound department waiting areas, and a brief study awareness leaflet to be 
distributed at/after the routine 16 week antenatal clinic appointment. Both poster and leaflet contain a 
QR code which can be scanned to view audiovisual content of research users talking about the study 
and why it is important. Thus, awareness of the study will already be high among individuals who may 
be invited to participate later in pregnancy.  
 
Bereaved participants (cases) 
Bereaved mothers/parents will be approached (ideally prior to discharge from the maternity unit) by a 
member of the clinical care team. A brief description of the study will be provided by their midwife, 
bereavement midwife or doctor, and consent to contact obtained to allow contact from a research 
midwife. Unless declined, a research midwife will either see the individual on the ward at a suitable time 
or contact the individual using their nominated preferred method of contact to discuss the study, provide 
the study information sheet, gain provisional consent and arrange an interview. Initial introduction to the 
study by a clinician known to the participant was viewed favourably by participants in MiNESS (36) and 
the study-specific PPI group. The co-investigators have extensive experience of recruiting bereaved 
parents to research studies. Our combined experience highlights that bereaved parents are keen to 
participate in research, even close to their time of loss. The co-investigators and coordinating research 
midwife will work closely with local research midwives to provide support for the local clinicians to 
minimise distress resulting from discussing the study. Bereaved individuals who attempt to self-refer 
direct to the study team will be advised to request referral by their midwife or doctor with whom the 
research team can confirm eligibility prior to recruitment.  

 
 
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Pregnant participants (controls) 
Pregnant people will be approached at an appropriately-timed routine antenatal appointment; for most 
individuals this will be following the routine fetal anatomy scan (18+0 to 20+6 weeks’ gestation (33)). 
This approach may be made by a clinician known to the potential participant or by a research midwife, 
many of whom recruited to the previous MiNESS study and are experienced in discussing stillbirth 
research with pregnant individuals. A brief description of the study will be provided and consent to 
contact obtained to allow follow up contact by a research midwife. If the individual declines participation 
or cannot be contacted (maximum three attempts over one week), another potential control participant 
will be identified and approached in the same manner until a suitable control participant is recruited. 
Self-referrals of pregnant individuals to the study team will not be accepted in order to minimise bias in 
control population recruitment. Individuals attempting to self-refer to the research team will be thanked 
and the random selection process explained.   
 
Following approach 
If the individual approached (bereaved or still pregnant) consents to being contacted by a research 
midwife they will be provided with a copy of the relevant participant information sheet (PIS) and consent 
form and asked to confirm their preferred mode of contact (telephone call, text message or email) and 
contact details using the study consent to contact (pre-recruitment) form.  
If no response to attempted contact is obtained, a maximum of two further contacts will be attempted, 
over the course of the following week. If no response is received to any attempted contact, no further 
attempts will be made and the participant’s contact details will be disposed of according to local NHS 
Trust procedures; if individuals subsequently self-initiate contact with the research team, the recruitment 
period can be resumed provided an interview can be arranged within the target time period. 
Upon successful contact, the research midwife will check the individual’s eligibility to participate, provide 
further details about the study and answer any questions the potential participant may have regarding 
the study. The individual will have up to one further week to decide whether or not to participate, if they 
are not ready to make that decision at the time of contact; this time is limited in order to attempt to 
preserve the accuracy of recalled information relating to their experiences and exposures around the 
time of fetal death diagnosis/target gestation. If the individual subsequently agrees to participate, a 
mutually agreeable date, time and format/place (e.g. Microsoft Teams call or face to face) for interview 
will be arranged. Interviews will be conducted by local research midwives. This builds on the model of 
recruitment in the original MiNESS study, which received positive feedback (36). Contact details will be 
retained until after interview, and only retained thereafter if specific consent to follow up contact is 

 
 
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received from the individual (see section 4.4.1), as there is no further participant involvement in the 
study after completion of the structured interview.  
 
6.3.1 Sample identification 
Bereaved mothers/parents (cases):  
Bereaved mothers/parents will be identified by the direct clinical care team. The research team at each 
site will actively engage with all relevant clinicians including, but not limited to, midwives including 
bereavement midwives, gynaecology nurses including miscarriage specialist nurses, obstetricians and 
gynaecologists, as appropriate for the particular care arrangements in their unit. They will ensure that 
local clinicians are aware of the study, its eligibility criteria, purpose of the study and what it would involve 
for participants as well as how to refer a patient (with their consent) to the research team.  
 
Pregnant people (controls): 
Potential control participants will be identified by a clinician from the local maternity care team, and 
eligibility checked prior to approach. Those involved in participant identification and eligibility screening 
must have current Good Clinical Practice (GCP) and information governance training, have received 
study specific training from the local PI or delegated other, be listed on the site delegation log as 
participant identifiers and follow all relevant Trust policies. Potential participants will be identified from 
the maternity unit’s booking list, according to the SOP for identification and approach of potential control 
participants in order to avoid recruitment bias. The exact implementation details of this SOP will depend 
on local maternity unit information systems and access controls. Study screening/approach, as well as 
recruitment, logs will be maintained at each study site and the number of potentially eligible individuals, 
number of people approached and number of people recruited will be reported. Recruitment ratios for 
each participant group will be monitored by the TMG. 
The screening log will be cross-checked prior to approach of any potential control participants in order 
to avoid re-approach of individuals already approached/recruited. Where an individual was previously 
approached to participate in the study as a control participant, whether they participated or not at that 
time, and subsequently becomes eligible for inclusion as a bereaved mother/parent participant, the 
immediate clinical care team will sensitively provide a further no-obligation opportunity to participate 
under the new circumstances.  
No participant identification centres or disease registries will be used. While awareness of the study will 
be raised among the general maternity unit population via study materials (poster, leaflet) and the study 
will be listed on a clinical trials registry, no participants will be recruited via such sources. No payments 
will be made to participants for their participation. 

 
 
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6.3.2 Consent 
The majority of recruitment and interviews will be conducted remotely (Microsoft Teams call). Due to 
this, it will not be practical to obtain contemporaneous written informed consent from all participants.  
All potential participants approached will be provided with a copy of the REC-approved PIS and study 
consent form in advance of the agreed interview. These documents will be professionally translated into 
Arabic, French and Urdu following REC approval; these languages have been chosen according to UK 
Census data (37) on first and second language skills and the known epidemiological distribution of 
(early) stillbirth (9). Telephone translation services will be available for other languages (or where the 
individual does not read that language) where appropriate to ensure that (potential) participants have 
appropriate understanding of the information contained in the PIS and consent form. The PIS and verbal 
information given to potential participants will emphasise that participation is voluntary and that they can 
change their mind if they wish. Researchers will ensure that participants have a good understanding of 
the pros and cons of participating, and what participation entails as well as answering any questions 
relating to the study to the participant’s satisfaction before obtaining informed consent. It is recognised 
that individuals recruited to research studies in pregnancy, and particularly after bereavement, are 
particularly vulnerable and the highest standards of research practice will be ensured. 
At the time of the interview, where conducted remotely, virtual consent will be sought according to the 
SOP for documenting virtual consent. The interviewer (research midwife) will obtain verbal permission 
to make a short audio(visual) recording of the participant’s consent to participate using Microsoft Teams. 
Consent to recording will be stated before and also once recording starts. The participant and researcher 
(and interpreter if applicable) will verbally identify themselves. The researcher will then read the consent 
form item by item to the participant, and ask the participant to verbally indicate consent (or not) for each 
item, ending with confirmation of overall consent to participate in the study. The researcher will verbally 
confirm the end of the recording. The recording will then be stopped.   
At the end of the Microsoft Teams call the research midwife will review the audio(visual) consent file to 
ensure it has saved correctly and stored securely on the local hospital secure data server according to 
the relevant Sponsor SOPs/Guidelines. A paper copy of the study consent form will be generated 
indicating the file storage location of the audio(visual) consent record on the local NHS Trust server 
(subject to at least daily back up); electronic records of consent will be named using the participant’s 
unique study identification number. An electronic scan of this paper record will be sent by encrypted 
email to the participant from the research midwife’s NHS Trust email address. A copy of the sent email 

 
 
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with attachment will be stored as a PDF along with the electronic consent recording. The email 
(containing the record of consent) will then be deleted from the research midwife’s sent emails folder.  
In the unlikely event of a failed recording, the participant will be contacted and the verbal consent 
process re-recorded (or arrangement made for a paper copy of the consent form signed and returned). 
The same process will be followed in the unlikely event of a lost/corrupted record of verbal consent 
during the study/data retention period. This is considered to be an unlikely scenario as all consent 
recordings will be stored on the local sites’ NHS Trust servers which will be regularly backed up. In the 
event of not having been able to contact the participant to re-record consent, and in the absence of a 
request from the participant to withdraw from the study, informed consent to participate will be evidenced 
by meticulous contemporaneous records of the approach and consent process, and implied by virtue of 
the participant’s active participation in the study interview.  
Where the study interview occurs face to face, the participant will complete a paper consent form and 
be provided a paper or electronic copy of the consent form (according to the process described above) 
according to the individual participant’s preference.  
Where an interpreter is used for translating during consent procedures, whether in person or remotely 
their professional details (name and interpreter identification code as issued by their employing 
translation company) will be recorded in the same way as for researcher/participant; friends and family 
members will not be used to translate for the consent/interview process. Participants will be offered a 
copy of the completed paper consent form. 
If an individual declines consent to participate in the study overall or in any non-optional consent clause 
(see consent form) any audio(visual) or paper record of the attempted consent procedure will be 
deleted/destroyed in line with the Trust’s local policies. A record of the screening and attempted 
recruitment will be kept in the study screening log to prevent further approaches. 
 
Individuals without capacity to provide informed consent to participate after the above steps (including 
translation) are taken, are not eligible to participate. Assessments of capacity will be made informally by 
the local research midwife who may seek support from the local Principal Investigator if needed. Any 
audio(visual) or paper record of the attempted consent procedure will be deleted/destroyed in line with 
the Trust’s local policies if the individual is deemed to not have capacity to consent. A record of the 
screening and attempted recruitment will be kept in the study screening log to prevent further 
approaches.  
 

 
 
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7 
ETHICAL AND REGULATORY CONSIDERATIONS 
7.1 
Assessment and management of risk 
The interview will take place within the first few weeks following a bereavement (which is recognised to 
be an extremely traumatic and difficult period). If the recruitment process and the interview itself is not 
conducted in a sensitive and empathetic manner, there is the potential for participation in this study to 
exacerbate the grieving process. In order to mitigate this, the research midwives will be carefully 
selected and trained not only in the conduct of the interview, but also in aspects of bereavement support. 
Researchers will be trained to interview in a manner that upholds the dignity of participants at all times; 
while sensitive information is being collected, participants will be reassured that they can choose to not 
answer, to skip (a) question(s) or to stop the interview at any time. Similarly, while most interviews will 
take between 1-1.5hours to complete, sensitivity and flexibility is required, particularly when interviewing 
recently bereaved individuals who may need longer to adequately describe their experiences. 
Information will be made available to participants regarding local bereavement/counselling support as 
required. Feedback from participants in the original MiNESS, Auckland Stillbirth and Sydney stillbirth 
studies suggests that rather than finding the process a burden, participants appreciated taking part in 
the research, and appreciated the opportunity to talk about their baby and their experience. Bereaved 
members of the study-specific PPI group have emphasised that such participation may be viewed as a 
way to "make their baby's life count". 
There is a risk that individuals approached to take part in the study in ongoing pregnancies (control 
participants) may be dissuaded from participating due to a fear of "tempting fate", and may experience 
some increase in distress in relation to mention of the potential of stillbirth in any pregnancy. However, 
significant proportions of individuals approached to participate as potential "control" participants in each 
previous similar study (Auckland Stillbirth Study, Sydney Stillbirth Study and MiNESS) did so and 
provided positive feedback on their experience of participation. Members of the study-specific PPI group 
have expressed that study materials emphasising the need to learn from healthy pregnancies in order 
to prevent stillbirths overall would be received as a positive message and would be more likely to 
encourage individuals approached to participate, particularly if they were made aware of the study in 
advance of being approached to participate. As a result we have co-produced a study information leaflet 
to raise awareness of the study and have named the study to emphasise the role of mothers/parents as 
experts, working with researchers to prevent stillbirths overall. 
The majority of interviews are expected to occur via video call. However, if potential participants wish to 
have a face to face interview, it is appropriate that this can be facilitated in a location that is not likely to 
increase participant distress. The risks of lone working in an off-site location should be carefully risk 
assessed according to the local hospital Trust lone working policy which is already common practice in 
midwifery teams (for example community midwife home visits or home births). Recommendations for 

 
 
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safe lone working include review of any documented safeguarding issues, and use of a buddy system. 
Where significant risks are identified, online interview should be recommended; if not 
acceptable/possible for the potential participant the local research midwife should consider being 
accompanied at interview by another suitably trained research team member or, if serious concerns 
remain, consideration of non-recruitment.  
7.2  
Research Ethics Committee (REC) and other Regulatory review & reports 
NHS Research Ethics Committee (REC) and Health Research Authority (HRA)/Health and Care 
Research Wales (HCRW) approval will be obtained prior to the study commencing. As it is unclear which 
sites will participate in the study after final approval, while overarching REC and HRA/HCRW approval 
is being applied for initially including research sites that have already expressed an intent to participate, 
other sites are expected to be recruited after approval. Thus, amendment(s) will be submitted to enable 
the REC and HRA/HCRW teams to review the intended additional recruitment sites when capacity to 
join the study is confirmed. 
Before the start of the study, a favourable opinion will be sought from an NHS REC for the study and all 
the supporting documents including the protocol, information sheets, informed consent forms and other 
relevant documents. The study team will be responsible for the maintenance of a study site file, in which 
all current and superseded study documents will be retained. Also contained in the site file will be the 
approval documentation including correspondence with relevant authorities such as the HRA/HCRW 
and REC. 
All correspondence with the REC and HRA/HCRW will be retained in the site file. The study team are 
responsible for producing progress reports throughout the study, including annual reporting (APR) to 
REC as required. The Chief Investigator will notify the REC of the end of the study, and will submit a 
final report with the results, including any publications, to the REC within 12 months of the end of the 
study. If the study is ended prematurely, the Chief Investigator will notify the REC, including the reasons 
for the premature termination. 
No participants will be enrolled into this research study at any site prior to the study being reviewed by 
the relevant regulatory authorities and receiving HRA/HCRW and REC approvals, as well as approval 
from the relevant R&D office. The study will be conducted in accordance with the Declaration of Helsinki, 
REC and HRA/HCRW approvals and the requirements of the Sponsor/local NHS Trust R&D 
department. 

 
 
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7.2.1 Regulatory Review & Compliance  
Before any site can enrol patients into the study, the Chief Investigator/Principal Investigator or designee 
will ensure that appropriate approvals from participating organisations are in place.  
7.2.2 Amendments  
Any amendments to the to the study shall be reviewed by the Sponsorship Team prior to submission. 
Any non-substantial amendments shall be notified to the HRA and any substantial amendments, along 
with amended documentation, shall be approved by the REC, and HRA, prior to implementation as per 
nationally agreed guidelines. The Chief Investigator or designee will work with the R&I department to 
put the necessary arrangements in place to implement the amendment and to confirm their support for 
the study as amended. The Chief Investigator or designee will work with sites (R&D departments at 
NHS sites as well as the study delivery team) so they can put the necessary arrangements in place to 
implement the amendment to confirm their support for the study as amended. 
 
7.3  
Peer review 
The proposed study has been subject to rigorous internal and external independent expert peer review 
through the Manchester Academic Health Sciences Centre and the funding body, National Institute for 
Health and Care Research. The study has been modified in line with expert feedback.  
7.4  
Patient & Public Involvement 
The research question - understanding the role of modifiable “lifestyle” factors in stillbirth prevention – 
was identified as top research priorities in the James Lind Alliance (JLA) Priority Setting Partnerships 
(PSP) for stillbirth (led by Prof. Heazell) (4), and for miscarriage (5). This question was proposed by 
individuals from all key stakeholder groups including those who identified as parents or family/friends. 
Stillbirth prevention and modifiable risk have also arisen as consistent themes in public engagement 
activities coordinated/participated in by Prof. Heazell and Dr. Higgins including the Still Born project, 
Before You Were Born event and Still Life workshops. Thus, the proposed project addresses a research 
user-defined research question. 
A multi-ethnic study-specific PPI panel, representative of potential bereaved and pregnant study 
participants, was convened to inform the ongoing design of this study. Members provided input on the 
study question, scope (including expanding the case definition to include those bereaved by immediate 
neonatal death), study design (including specific input on study name, methods of approach/recruitment, 
widening participation and acceptability of proposed research areas/interview questions), terminology 

 
 
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and language sensitivity within the study interview and accessibility (including use of translators and 
translated study materials) which was used to inform the study protocol.  
Key messages received from our PPI work to date include: 
● The term “stillbirth” (rather than “miscarriage”) better describes baby loss at 20-28 weeks’ 
gestation as the baby is viewed as a “person” at that stage.  
● The terms “bereaved mother/parent” and “pregnant woman/person” are the preferred terms to 
recognise the roles/identities of birthing people with and without bereavement through stillbirth. 
● The second trimester of pregnancy is viewed as a time to “relax” having “avoided [early] 
miscarriage" and “before [the risks of] late pregnancy” kick in. 
● Stillbirth risk reduction is rarely explicitly discussed with medically "low risk" prospective 
mothers/parents. 
● Pregnant people are motivated to improve the health of their baby and would be willing modify 
their lifestyle to reduce stillbirth risk. 
● Lifestyle modifications are preferable to pharmacological/other interventions in pregnancy. 
● Pregnancy research involving lifestyle modification was viewed positively, but care must be 
taken to avoid inferring blame. 
● Pregnant people receiving maternity care at participating hospitals should be made aware of the 
ongoing research study and its purpose before the time at which they may be approached to 
participate. 
● Bereaved mothers/parents and pregnant women/people may be more likely to participate in the 
study if approached by an individual known to them/at a routine appointment, rather than by 
telephone call. 
● Audiovisual study information leaflets/videos showing other mothers/parents of diverse 
backgrounds talking about the research are preferred to traditional or animated study 
promotional materials.  
● Virtual interviews via video call are preferred to face to face meetings at hospital sites or having 
a stranger (researcher) visit their home; the option to have a face to face meeting should be 
available to those who want it. 
● Bereaved parents are keen to honour their baby by telling their baby’s story; interviews should 
be allowed to continue to enable the participant to tell the researchers anything they feel is 
important.  
● Baby’s name, where one has been given, should be used during the interview. Participants 
should be referred to by name and not as “Mum”. 

 
 
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● Potentially sensitive topics, such as personal hygiene practices, sexual activities and vaccination 
uptake are acceptable and important to be addressed in the study questionnaire; these should 
be asked along with other questions so as not to imply shame or “difference”. 
The study proposed has been directly informed by this PPI work, to address the specific needs of the 
current study population (those with baby loss between 20-28 weeks’ gestation). The research study 
has been developed with, and refined by, Co-investigator Storey (Lay researcher and PPI co-lead). 
Members of the study-specific PPI group have reviewed and contributed to the study questionnaire 
wording/design, IRAS application and this study proposal and have accepted membership of the SSG.  
The trial advisory group (comprising study-specific PPI group representatives, charitable/community 
interest organisation stakeholders and international advisors with expertise in stillbirth research as equal 
members) will meet as required to oversee the successful conduct of the study. Study-specific PPI group 
representatives' expertise will be sought to understand, and overcome, any barriers encountered in 
study recruitment/participation, and to determine/create a lay accessible public dissemination strategy 
for the study findings. 
The study-specific PPI group members will be kept engaged throughout the study period with regular 
progress updates and will reconvene after initial data analysis is completed to discuss study findings, 
gain research-user insight and finalise the dissemination strategy.  
7.5 
Protocol compliance  
The research team will be vigilant in protocol deviations and will record them on a study specific 
deviation log which will be regularly assessed by the PI 
Deviations that may affect the safety, physical or mental integrity of participants or scientific value of the 
study will be reported to the study sponsor via research.sponsor@mft.nhs.uk by the MFT research team.  
Deviations from the protocol which are found to frequently recur are not acceptable, will require 
immediate action and could potentially be classified as a serious breach and should also be reported to 
the sponsor without delay. 
Compliance with the study protocol will be ensured by a number of procedures: 
7.5.1 Set-up and training 
The local midwives will already be experienced in obtaining informed consent for research studies and 
hold current GCP certification. They will be trained and supported by the coordinating research midwife 
and co-Investigator team to obtain study-specific informed consent from participants, in the study-
specific interview process and in use of the eCRFs. The local midwives will extract data from clinical 

 
 
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notes and enter data from the interviews and medical notes reviews onto a customised online study 
REDCap database; training will be provided on how to use the study database eCRFs. The coordinating 
research midwife can be contacted by local research team members for day to day queries on these 
issues. 
The Chief investigators and co-investigators can be contacted if there are any concerns regarding 
adherence to the protocol and to deal with any issues arising from the investigations (7.5.2-7.5.3).  
7.5.2 Data processing and monitoring  
Data will be collected directly onto bespoke eCRFs via the REDCap study database. Data extracted 
from the medical records will be checked for validity in 10% of records from each site every six months. 
Where errors are detected, these can be corrected at the time of cross-checking. If errors in more than 
10% of data fields are detected at a particular site, all records created in that six month period will be 
locally cross-checked and amended as required; a file note will be made to detail changes made and 
shared with the Chief Investigator so that any need for targeted local staff training can be assessed.  
7.5.3 Monitoring 
The study will be subject to the audit and monitoring regime of Manchester University NHS Foundation 
Trust in line with applicable MFT SOPs and policies. The study will have, as a minimum, an annual 
survey sent out for completion by a member of the research team. 
7.6 
Data protection and patient confidentiality  
● All investigators and study site staff must comply with the requirements of the Data Protection 
Act 2018 with regards to the collection, storage, processing and disclosure of personal 
information and will uphold the Act’s core principles. 
● Audio(visual) recordings of verbal consent and electronic study logs will be uploaded direct to 
a restricted access folder on the local secure research data server of the recruiting NHS Trust 
at the time of recruitment.  
● Hard copies of consent forms (where applicable) will be stored in a locked cabinet, in the local 
site research office with access controls (swipe card, passcode or key).  
● Consent records (records of verbal consent or physical consent forms), consent to contact 
details printed study log documents will be retained in local site files and stored according to 
the Sponsor’s SOPs/guidelines at the time of study completion.  
● All participants will be allocated a coded, depersonalised study identification number upon 
entry to the study. All data recorded on eCRFs and submitted to the central research team at 

 
 
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MFT will be identified only by this unique study identification number. The link between the 
study identification number and participant identity will be stored on:  
● The local study recruitment log: during study recruitment and follow up this will be an 
encrypted, password protected electronic file, which will be uploaded to a restricted 
access folder on the local NHS Trust server (a site file note will detail where this file is 
stored). After study follow up ends, the log will be printed and stored in the ISF, and the 
electronic file deleted.  
● The paper/electronic record of consent: paper consent forms will be stored at the local 
research site where they will be subject to physical access controls. Electronic consent 
records will be stored in a restricted access folder on the local NHS Trust server with 
access restricted to only those who require it for their study role.  
● Access to pseudonymised data, study screening/recruitment logs, contact details and consent 
forms will be restricted to the minimum number of individuals necessary for quality control, 
audit, and analysis. In particular, local research teams will only have access to records 
pertaining to recruits from their own NHS Trust.  
● All electronic records containing patient identifying information, including audio(visual) consent 
records, will be stored only on NHS Trust servers with a minimum of daily back up. No 
electronic study data should be stored on USB sticks or laptops prior to complete 
anonymisation.  
● The coordinating research midwife and chief investigator will have access to all study records 
in REDCap for the purpose of supporting local research site staff with eCRF data entry issues 
and data monitoring. They will have the ability to raise data queries (e.g. in the case of internal 
contradictions/inconsistencies, missing data or out of range/incorrect format data within 
individual eCRFs).  
● Direct access to pseudonymised data will be granted to authorised representatives from the 
Sponsor, host institution and the regulatory authorities to permit trial-related monitoring, audits 
and inspections in line with participant consent. 
● The study data will remain the property of Manchester University NHS Foundation Trust. The 
Chief Investigator will be the data custodian. A complete copy of the study pseudonymised 
data will be kept on the MFT secure IT server at the end of the study. Local sites’ individual 
site files will be stored locally. 
7.7 
Indemnity 
The NHS indemnity scheme will apply to this study to ensure it meets the potential legal liability of the 
Sponsor, participating NHS Trusts, employers and Investigators/Collaborators for harm to participants 

 
 
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arising from the management, design and conduct of the research. No arrangements will be made for 
the payment of compensation in the unlikely event of harm.  
7.8 
Access to the final study dataset 
At the end of the study data collection period, the pseudonymised electronic data set (including unique 
study ID numbers, but not the key to de-anonymise this) will be downloaded from the secure REDCap 
database and stored on a single data spreadsheet at MFT. It will be accessible only to the Chief 
Investigator and coordinating research midwife (until after resolution of all data queries and creation of 
derived indices e.g. indices of multiple deprivation and air pollution exposure [from postcodes], ages 
and gestations [from dates of birth] at which point the file will be locked and coordinating research 
midwife access removed). A record of patient’s names and their unique subject identifier will be kept as 
an electronic study file that will be stored within the confines of each participating site, behind a firewall 
on password protected IT server to allow for the study investigators, if needed, to query original records. 
The study statistician will not have access to this record or any identifiable patient data, they will receive 
a fully anonymised data set for analysis. The study identification number and identifiable information will 
be removed prior to analysis to anonymise the database and be replaced with a unique sequential 
number commencing at 1.  
 
Local researchers and co-investigators will not have access to the full dataset until after publication, 
after which point the full dataset, without study identification numbers and with all directly/indirectly 
identifiable data removed (completely anonymised), will be made available to all co-investigators and 
made freely available via a central research data repository upon publication of the primary research 
findings. Other researchers will be free to use this data to verify the research findings of this study and 
to answer related research questions, with appropriate attribution, under a creative commons licence.  
 
8 
DISSEMINIATION POLICY 
8.1  
Dissemination policy 
● Data arising from the study will be owned by Manchester University NHS Foundation Trust. The 
funders (National Institute of Health and care Research) will be acknowledged in all publications 
arising from this study, but will have no role in the conduct, analysis or interpretation of the study.  
● The study protocol, including statistical analysis plan, will be published.  
● The study-specific PPI group, will be consulted during analysis stages to determine an 
appropriate research dissemination strategy.  

 
 
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● On completion of the research, the data will be published in peer-reviewed journals. It is 
anticipated that this will be accompanied by publication of the completely anonymised data in an 
online research data repository. 
● Following completion of the research, the findings will be submitted for presentation at national 
and international conferences. 
● Study participants are advised within the PIS that they will be contacted with a copy of the study 
results if they give their consent for their contact details to be used for this purpose, and are 
advised of several social media accounts belonging to the study team and charitable stakeholder 
partners who will disseminate lay-accessible summaries of the study findings.  
● Key charitable partners, as well as the Maternal and Fetal Health Research Centre at University 
of Manchester will include lay summaries of the research findings on their social media channels. 
A study-specific twitter account will be established to share public study updates. Participants 
are advised to follow these channels for study updates.  
● The central study team will provide research updates to all participating sites, informing them of 
the study findings after analysis. 
● Any 
study 
manuscripts 
will 
follow 
the 
REDCap 
publication 
requirements 
(https://projectredcap.org/resources/citations/). 
 
8.2  
Authorship eligibility guidelines and any intended use of professional writers 
In accordance with guidelines created by The International Committee of Medical Journal Editors, all 
authors will have: 
● Made substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work; 
● Performed drafting of the work or revised it critically for important intellectual content; 
● Approved the final version of the article prior to publication;  
● Agreed to be accountable for all aspects of the work in ensuring that questions related to the 
accuracy or integrity of any part of the work are appropriately investigated and resolved. 
Anyone meeting the above criteria for work contributing to any publication will be included as authors. 
The study co-investigators are anticipated to be included as authors on all primary academic papers 
arising from this study. As appropriate, students working under supervision with anonymised data 
performing secondary analyses, and/or the lead research midwife may also meet criteria for inclusion 
as authors for certain primary academic papers and will be appropriately acknowledged. There is no 
intended use of professional writers. 
 

 
 
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9 
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IRAS 314658  
Mothers Working to prevent early stillbirth: 20-28 (MiNESS 20-28)   
Protocol V1.4 18/10/2023 
 
 
43 
10  
APPENDICIES 
10.1 
Appendix 1- Schedule of Events  
Procedures 
Screening 
Interview 
Case note 
review 
Pregnancy 
outcome  
Confirmation of eligibility 
x 
 
 
x 
Local approach of 
participant 
x 
 
 
 
Informed consent 
 
x 
 
 
Questionnaire 
 
x 
 
 
Demographics 
 
x 
x 
 
Medical history 
 
x 
x 
 
Outcome assessment  
 
 
 
x 
 
10.2 
Appendix 2 – Amendment History 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
N/A