Implementation of a Model for Predicting Early Pregnancy Outcome in Women With Pregnancy of Uncertain Viability: a Psychological Impact Study
Phase: NA
Conditions: Uncertain Viability of Pregnancy, Anxiety, Depression
Sponsor: Chelsea and Westminster NHS Foundation Trust

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 1 of 22 
 
IMPROVE study  
Ethics Ref: 17/WM/0362  
Date and Version No: 21th February 2017, Version 3.0  
 
 
Study Title:   
Implementation of a tool for predicting early pregnancy outcome in 
women with initial pregnancy of uncertain viability: a psychological 
impact study  
Chief Investigator: 
Dr Kim Lawson, MBChB (Hons) 
Clinical Research Fellow 
Early Pregnancy Assessment Unit  
Chelsea and Westminster Hospital 
369 Fulham Road, London SW10 9NH 
Email: kimlawson@nhs.net 
Telephone: 02033155070  
 
Investigators:  
Miss Cecilia Bottomley, MB BChir, MRCOG, MD 
Consultant Obstetrician and Gynaecologist  
Early Pregnancy Assessment Unit  
Chelsea and Westminster Hospital 
369 Fulham Road, London SW10 9NH 
Email: Cecilia.bottomley@chelwest.nhs.uk 
Telephone: 02033155070 
 
Miss Roshni Patel MBChB, MRCOG, MSc, PhD.  

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 2 of 22 
Consultant Obstetrician and Gynaecologist 
Sub specialist in Maternal and Fetal Medicine 
Chelsea and Westminster Hospital 
369 Fulham Road, London SW10 9NH 
Email: roshni.patel@chelwest.nhs.uk 
 
Sponsor:  
Chelsea and Westminster Hospital NHS Foundation Trust is the main 
research sponsor for this study. For further information regarding the 
sponsorship conditions, please contact: 
Research & Development Office 
Unit G2, Harbour Yard 
Chelsea Harbour 
London 
SW10 0XD 
Tel: 0203 315 6825 
Damon.foster@chelwest.nhs.uk 
Funder: 
No external funding required 
  
Chief Investigator Signature:   
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, host organisation, and members of the Research Ethics Committee, 
unless authorised to do so. 
This protocol describes the study and provides information about procedures for entry. Problems 
relating to this study should be referred, in the first instance, to the Chief Investigator.  
 
 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 3 of 22 
TABLE OF CONTENTS 
 
1. 
SYNOPSIS............................................................................................................................................... 5 
2. 
ABBREVIATIONS .................................................................................................................................... 5 
3. 
BACKGROUND AND RATIONALE ........................................................................................................... 6 
4. 
STUDY HYPOTHESIS .............................................................................................................................. 7 
5. 
AIMS AND OBJECTIVES ......................................................................................................................... 7 
6. 
STUDY DESIGN ...................................................................................................................................... 8 
6.1. 
Participant groups ........................................................................................................................ 8 
7. 
PARTICIPANT IDENTIFICATION ........................................................................................................... 11 
7.1. 
Study Participants ...................................................................................................................... 11 
7.2. 
Inclusion Criteria ........................................................................................................................ 11 
7.3. 
Exclusion Criteria ........................................................................................................................ 11 
8. 
STUDY PROCEDURES ........................................................................................................................... 11 
8.1. 
Recruitment ............................................................................................................................... 11 
8.2. 
Informed Consent ...................................................................................................................... 12 
8.3. 
Potential risks and benefits ........................................................................................................ 12 
8.4. 
Screening and Eligibility Assessment ......................................................................................... 13 
8.5. 
Discontinuation/Withdrawal of Participants from Study .......................................................... 13 
8.6. 
Definition of End of Study .......................................................................................................... 13 
9. 
INTERVENTIONS .................................................................................................................................. 13 
10. STATISTICS AND ANALYSIS .................................................................................................................. 14 
10.1. 
The Number of Participants ....................................................................................................... 14 
10.2. 
Description of Statistical Methods ............................................................................................. 14 
11. DATA MANAGEMENT ......................................................................................................................... 14 
11.1. 
Access to Data ............................................................................................................................ 15 
11.2. 
Data Recording and Record Keeping ......................................................................................... 15 
12. ETHICAL AND REGULATORY CONSIDERATIONS .................................................................................. 15 
12.1. 
Declaration of Helsinki ............................................................................................................... 15 
12.2. 
ICH Guidelines for Good Clinical Practice .................................................................................. 15 
12.3. 
Approvals ................................................................................................................................... 15 
12.4. 
Reporting .................................................................................................................................... 15 
12.5. 
Participant Confidentiality ......................................................................................................... 15 
13. FINANCE AND INSURANCE .................................................................................................................. 16 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 4 of 22 
 
Funding ............................................................................................................................................... 16 
13.1. ......................................................................................................................................................... 16 
13.2. 
Insurance .................................................................................................................................... 16 
14. PUBLICATION POLICY .......................................................................................................................... 16 
15. REFERENCES ........................................................................................................................................ 17 
16. APPENDIX ............................................................................................................................................ 18 
17. AMENDMENT HISTORY ....................................................................................................................... 22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 5 of 22 
1. SYNOPSIS 
 
Study Title 
Implementation of a tool for predicting early pregnancy outcome in women 
with pregnancy of uncertain viability: a psychological impact study 
Short Title/Acronym 
IMPROVE 
Study Design 
Single centre, non-blind randomised intervention study 
Study Participants 
Women diagnosed with an intrauterine pregnancy of uncertain viability 
(IPUVI) will be recruited to one of two groups: 
Group I – women randomised to receive prediction tool 
Group II – women randomised to not receive the prediction tool 
 
Planned Sample Size 
250 participants  
Planned Study Period 
2 years  
 
Objectives 
Endpoints 
 
Primary 
 
To assess whether providing an 
individualised risk prediction of early 
pregnancy viability, in women diagnosed 
with intrauterine pregnancy of uncertain 
viability, has a beneficial psychological 
impact during the time to final diagnosis  
 
 
Secondary  
To assess patient experience of the 
prediction tool 
 
To assess healthcare professionals 
experience of offering and providing more 
accurate information regarding pregnancy 
outcome to patients 
 
2. ABBREVIATIONS 
 
CI 
Chief Investigator 
CRF 
Case Report Form 
CWFT 
Chelsea and Westminster Hospital Foundation Trust 
EPAU 
Early Pregnancy Assessment Unit  
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HADS 
Hospital Anxiety and Depression Scale  

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 6 of 22 
HCP 
Healthcare Professional  
ICF 
Informed Consent Form 
IPUVI 
Intrauterine Pregnancy of Uncertain Viability  
NHS 
National Health Service 
NICE 
National Institute for Health and Care Excellence  
NRES 
National Research Ethics Service 
PI 
Principal Investigator 
PIS 
Participant/ Patient Information Sheet 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SOP 
Standard Operating Procedure 
 
3. BACKGROUND AND RATIONALE 
 
Early pregnancy can be a particularly distressing time for women and their partners, especially those who 
experience complications such as bleeding or pain. 10-28% of women seen in the early pregnancy 
assessment unit (EPAU) setting are diagnosed with a pregnancy of uncertain viability (IPUVI)1-5.  Such 
women have a pregnancy correctly sited within the uterus but the viability of the pregnancy cannot be 
determined at the initial scan. This finding may represent a normally developing (but early) pregnancy. 
However, approximately 50% of these pregnancies will eventually miscarry1,4,5. The current 
recommendation from The National Institute for Health and Care Excellence (NICE) is to offer a 
confirmatory scan after 14 days6.  
This 14-day interval between scans is a difficult time for patients. Studies have previously identified the 
negative impact on psychological health where early pregnancy complications arise2,3. We know that 
miscarriage is positively associated with grief, anxiety, stress, depression7 and even post-traumatic stress 
disorder (PTSD)8. Studies have also shown that this is not necessarily an immediate reaction as women 
with early pregnancy loss have met criteria for conditions such as probable PTSD and major depressive 
disorder at 3 and 6 months’ respectively after the event7,8. More recently, Richardson et al (2016) found 
that the diagnostic uncertainty in early pregnancy, as experienced with an IPUVI diagnosis, is associated 
with significant (p <0.001) heightened levels of anxiety compared with those who receive an early certain 
diagnosis of either a positive (ongoing pregnancy) or negative (miscarriage) outcome3. We want to find 
out whether this psychological response to an uncertain diagnosis can be modified by offering more 
detailed prognostic information to women.  
NICE Clinical Guideline CG154(2012) does not recommend specific tools or scoring systems to predict the 
viability of intrauterine pregnancy6. However, NICE Evidence Update 71(2014) suggests the availability of 
more information (prior to repeat ultrasound) on which to base estimates of viability in early pregnancy, 
could be useful and may benefit patients’ psychological health9. Published models and scoring systems 
for predicting outcome do exist with excellent performance results for the test populations5,10. One 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 7 of 22 
randomised controlled trial (RCT) looked at psychological outcomes when women were randomised to 
receive a prediction of their pregnancy outcome through means of a validated blood test. The results 
showed that anxiety levels were significantly reduced (p=0.04) in those who received the prediction of 
pregnancy outcome. The authors concluded that even if further information is not definitive, women 
benefit psychologically from tests that give them an indication of what a subsequent ultrasound might 
show2.  
We have previously developed, validated and published a mathematical tool to predict pregnancy 
viability after diagnosis of IPUVI (549 participants)5. The tool (which takes account of maternal age, 
vaginal bleeding score and ultrasound measurements) is established as an accurate research tool having 
been externally validated in a different test population10. Having established its performance, we now 
wish to provide women with this individualised prediction of their pregnancy outcome. If psychologically 
beneficial (and not harmful) this tool may help up to a third of the EPAU population.  
There is an increasing need for a shift towards patient-centred care in the early pregnancy setting12. It 
has been suggested that health professionals underestimate the psychological impact of early pregnancy 
complications for women and couples13.  
An audit within the EPAU at Chelsea and Westminster was conducted assessing the variation in 
information given to women by the medical professional who diagnoses IPUVI at the initial ultrasound. 
This demonstrated wide inter-professional differences. The most commonly reported explanation of the 
ultrasound findings to the woman was “it is too early to tell.” 2/3 of the healthcare professionals (HCP) 
stated that they offered different intervals to the subsequent ultrasound (i.e. 7 days, 10 days or 14 days) 
to different women, all with the same IPUVI diagnosis. When asked about likely percentage outcome of a 
viable pregnancy by the end of the first trimester in all IPUVI diagnoses, responses were varied between 
50 to 70%, others were “unsure”. 80% of HCP’s felt they would find it beneficial to be able to offer a 
predicted outcome of the pregnancy being viable at the follow-up ultrasound. This ambiguity in advice 
that these women receive when given an uncertain diagnosis may have an impact upon psychological 
well-being. 
4. STUDY HYPOTHESIS  
 
We hypothesise that providing women diagnosed with IPUVI with a percentage likelihood of ongoing 
viability of their pregnancy, will result in improved psychological well-being (reduced anxiety and 
depression) at the time of the follow-up ultrasound.  
5. AIMS AND OBJECTIVES 
 
Objectives 
Outcome Measures/Endpoints  

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 8 of 22 
Primary Objective 
 
 
1. To assess whether providing an individualised 
risk prediction of early pregnancy viability, in 
women diagnosed with intrauterine pregnancy 
of uncertain viability, has a beneficial 
psychological impact during the time to final 
diagnosis  
Secondary Objectives 
 
 
 
2. To assess patient experience of the prediction 
tool  
3. To assess healthcare professionals experience of 
offering and providing more accurate 
information regarding pregnancy outcome to 
patients  
 
5.1.  Aims 
The aims of this study are:  
1. To assess and compare if there is any significant difference in symptoms of anxiety and 
depression during the uncertain period, as measured by the Hospital and Anxiety Depression 
Score in two groups of women all diagnosed with IPUVI. The two groups will be; 1) women 
randomised to receive the prediction tool and 2) women randomised to not receive the 
prediction tool.   
  
2. To assess and compare whether the symptoms of anxiety and depression in the two groups of 
women change over three defined time points: immediately after the initial ultrasound/ 
diagnosis, at 72 hours post ultrasound and immediately prior to the follow-up ultrasound at 14 
days.  
 
3. To assess the patient experience during the study period by applying a self-reported experience 
questionnaire on the acceptability and perceived usefulness of the prediction tool, in those 
women who receive it. The questionnaire has been developed by the study investigators using 
modified versions of the Technology Acceptance Model by Davis et al, 1989.  
6. STUDY DESIGN 
 
This will be a single centre, non-blind, randomised intervention controlled trial.  
6.1. Participant groups 
 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 9 of 22 
A total of 250 eligible women with an ultrasound classification of IPUVI at Chelsea and Westminster 
Hospital will be identified and recruited to the study. Women will participate in one of the following 
groups: 
 
Group I (intervention) – women randomised to receive the prediction tool (125 participants) 
 
Group II (control) – women randomised to not receive the prediction tool  (125 participants) 
 
6.2. Data collection tools 
Data will be collected from women at three points during the course of the study (see flow diagram). A 
single, validated scale will be used for data collection regarding psychological well-being: - 
The Hospital Anxiety and Depression Scale (HADS), (Appendix 1, Zigmond and Snaith 1983) 
Participants will also be invited to give a free text response to detail any additional information arising 
from the questions they have been asked in the HADS questionnaire.  
Each questionnaire will take approximately 5-10 minutes to complete.  
The questionnaires will be sent to participants via email (or post if participants do not have access to 
email). If they do not initially respond the researcher may send a maximum of two email reminders and 
contact them by telephone on one occasion with prior consent from the participant. If they do not 
respond following these reminders they will be withdrawn from the study.  The local researcher will 
monitor the progress of each participant’s pregnancy prior to sending out the questionnaires. Women 
who are known to have undergone termination of pregnancy prior to completion of all three 
questionnaires will be withdrawn from the study and not contacted with further questionnaires. 
Participants in Group I will also be invited to complete a patient experience questionnaire at the end of 
the study period to assess their perceived acceptability and usefulness of the tool. This has been 
developed specifically for this study using modified versions of the Technology Acceptance Model (Davis 
et al 1989) (Appendix 2)14.  
 
6.3 Study Centres 
Single centre recruitment will take place at Chelsea and Westminster Hospital.  
Consecutive women diagnosed with IPUVI will be approached during the recruitment period.  
 
 
 
 
 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 10 of 22 
 
 
6.4 Participant journey  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All women with diagnosed IPUVI invited 
to participate  
Patients decline to participate. Remain 
in routine care pathway. 
Participants consent to randomisation 
or decline randomisation   
Women randomised to either receive or 
not receive the prediction tool by 
random computer generated program 
GROUP I (INTERVENTION)  - 
RANDOMISED TO RECEIVE THE 
PREDICTION TOOL  
GROUP II (CONTROL)  - RANDOMISED 
TO NOT RECEIVE THE PREDICTION 
TOOL  
Participants complete baseline HADS 
questionnaire (HADS-1) immediately 
following initial ultrasound diagnosis of 
IPUVI and risk prediction 
GROUP I recruits complete second HADS 
questionnaire (HADS-2) at 72 hours  
GROUP I participation complete 
GROUP I recruits complete third HADS 
questionnaire (HADS-3) immediately 
prior to routine follow-up scan (at 14 
days)  
Participants are given individualised risk 
prediction of pregnancy outcome 
following initial ultrasound 
Participants complete baseline HADS 
questionnaire (HADS-1) immediately 
following initial ultrasound diagnosis of 
IPUVI  
GROUP II recruits complete second 
HADS questionnaire (HADS-2) at 72 
GROUP II recruits complete third HADS 
questionnaire (HADS-3) immediately 
prior to routine follow-up scan (at 14 
days)  
GROUP II participation complete 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 11 of 22 
7. PARTICIPANT IDENTIFICATION 
7.1. Study Participants 
All women (both elective and emergency admissions) seen in the EPAU at Chelsea and Westminster 
Hospital with a diagnosis of IPUVI will be approached to consider participation following their initial 
ultrasound.  
7.2. Inclusion Criteria 
 
 
Age 18 years+  
 
Diagnosis of IPUVI on initial ultrasound  
7.3. Exclusion Criteria 
 
The participant may not enter the study if ANY of the following apply: 
 
Current mental health condition (anxiety, depression, eating disorder). The condition will be 
considered current if it has required one or more consultations with a medical professional 
(including a psychologist) over the past 6 months (women with past mental health condition will 
not be excluded) 
 
The patient is planning a termination  
 
Multiple order pregnancies 
 
Women who in the opinion of the researcher by virtue of language or learning impairment would 
be unable to give fully informed consent to the study  
8. STUDY PROCEDURES 
8.1. Recruitment 
Potential participants will be identified on a daily basis by those that regularly perform ultrasound scans 
within the department; sonographers, nurse specialists, research fellows and consultants. Once 
identified, they shall be approached by the local researcher for a face-to-face consultation who will 
confirm their eligibility criteria and explain the study. In addition, the detailed patient information sheet 
(PIS) will be provided before taking informed written consent. Clinicians who perform ultrasound scans 
out of hours, will be notified of the study and asked to inform eligible women about the study and obtain 
consent for the local researcher to contact them the next working day.  

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 12 of 22 
8.2. Informed Consent 
Participants will sign and date the informed consent form (ICF), before any study specific procedures are 
performed. Written and verbal versions of the PIS and ICF will be presented to the participants detailing 
the nature of the study and what it will involve for the participant. It will clearly state that the participant 
is free to withdraw from the study at any time for any reason without prejudice to future care, and with 
no obligation to give the reason for withdrawal. A copy of the signed ICF will be given to the participant, 
and a copy of the signed ICF will be placed in the patient’s medical notes. The original signed form will be 
retained at the study site in the Investigator Site File. The participant will be allowed adequate time to 
consider the written information before giving their consent.  
8.3. Potential risks and benefits 
Potential benefits 
Patient specific 
This study will confirm whether this prediction tool is of clinical and psychological benefit to the patient.  
Women may find the questionnaires they are asked to complete prompt them to seek help earlier for 
conditions which may otherwise have gone untreated such as anxiety and depression. In addition, they 
may find it therapeutic to be able to express their opinions, emotions and feelings during the period of 
uncertainty.  
Resource specific 
If the study shows that the prediction tool is acceptable to patients (as well as being accurate in terms of 
the actual pregnancy outcome) this will allow units to more appropriately triage follow-up plans were 
resources are limited.  
Following the study, we anticipate that the use of the tool could be extended to other clinical sites to aid 
the management and expectations of women diagnosed with IPUVI. The NICE Evidence Update 
specifically refers to this prediction tool and it is anticipated that this will be a nationally recommended 
tool if validated in this study.  
Potential risks/ burdens 
No physical risks will be incurred by participation in the study. 
Recruited women will not be expected to have any additional visits to the hospital during the study, over 
and above usual care.  
We are aware that when conducting a study of mental health symptoms, we could potentially identify a 
woman with an undiagnosed mental health condition, issues of self-harm or potential harm to others. 
The CI will check the survey responses regularly and will highlight any of serious concern to CB. The CI 
will then contact the woman directly to discuss her responses. She will be encouraged to see her GP if 
deemed necessary. If the woman does not wish to see her GP or there is continued concern from the 
local researcher the confidentiality clause may need to be broken in the interest of safety of the woman 
and others. The CI will then contact the woman’s GP directly after informing the patient of their intended 
actions, to report their concerns. 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 13 of 22 
It is possible that the women will not perceive any individual benefit from participating in this study.  
8.4. Screening and Eligibility Assessment 
Participants will be asked the eligibility questions prior to obtaining informed consent and a checklist will 
be completed for each participant which will be attached to the consent form in the study folder. 
8.5. Discontinuation/Withdrawal of Participants from Study 
Each participant has the right to withdraw from the study at any time. In addition, the CI/PI may 
discontinue a participant from the study at any time if the investigator considers it necessary for any 
reason including: 
 
Ineligibility (either arising during the study or retrospectively having been overlooked at 
screening) 
 
Withdrawal of consent 
 
Non-response to the questionnaires despite reminder emails and/or a telephone call with prior 
consent obtained to contact the patient  
 
Confirmation of pregnancy termination prior to completing 2nd or 3rd questionnaire  
 
If a participant withdraws from the study, data already collected with consent will be retained and used 
in the study but no further data will be collected or any other research procedures carried out on or in 
relation to the participant. The reason for withdrawal (if provided) will be recorded in the case report 
form (CRF). 
8.6. Definition of End of Study 
The end of the study will be when the desired number of women are recruited in all groups or at the end 
of a 12 month recruitment period, whichever is sooner. It is anticipated that the recruitment, follow-up 
and analysis will take no longer than 24 months. 
9. INTERVENTIONS  
 
All recruited women will be asked to provide data at three stages: 
1. At initial diagnosis  
All women will be asked to complete the HADS questionnaire (HADS 1).  
Women recruited to Group I will be provided with an individualised prediction of their pregnancy 
outcome (following informed written consent to be randomised) before completing the first HADS 
questionnaire.   
2. 72 hours following diagnosis  

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 14 of 22 
All women will be sent the HADS questionnaire (HADS 2). 
3. At follow-up (14 days)  
All women will be asked to complete the HADS questionnaire (HADS 3) prior to their follow-up scan. 
All women in Group I will be asked to complete a patient experience questionnaire at the end of the 
study period.  
 
10. STATISTICS AND ANALYSIS 
10.1. 
The Number of Participants  
 
To calculate the sample sizes, power calculations were performed on the HADS scale. Puhan et al (2008) 
report the minimal important difference in HADS scores is 1.5 units for a significance level of 0.05 and a 
statistical power of 80% when considering an intervention. Based upon this assumption and a common 
standard deviation of 4 points, 125 women are needed for each group (total 250 women). A drop-out 
rate of 10% is anticipated.  
10.2. 
Description of Statistical Methods 
A statistician will be consulted to assist in analysis of the data collected from the study. 
The following statistical analyses will be performed:   
 
Descriptive statistics will be used to compare the two groups in terms of baseline demographic 
characteristics 
 
Continuous variables normally distributed will be described reporting mean and standard 
deviation, otherwise median and interquartile range will be used. Categorical variables will be 
reported with frequency tables. 
 
To compare HADS scores between groups I and II, the t-test will be performed for continuous 
variables normally distributed, otherwise the Mann-Whitney U test will be used.  The Chi-
squared test will be used for categorical variables.  
A statistically significant difference will be considered as a p-value <0.05. The data will be checked for 
abnormalities, spurious and missing data. These will be coded separately and treated accordingly. 
Analyses will be carried out using Stata statistical software, Release 14 (StataCorp, College Station, TX). 
Throughout the study (and afterwards), the research investigators will welcome inspections and 
monitoring of the conduct of the research to ensure that the quality of the research is upheld. This 
includes offering direct access to any documents. 
11. DATA MANAGEMENT 
 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 15 of 22 
11.1. 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor or host institution for 
monitoring and/or audit of the study to ensure compliance with regulations. The study may be 
monitored, or audited in accordance with the current approved protocol, ICH GCP, relevant regulations 
and standard operating procedures. 
11.2. 
Data Recording and Record Keeping 
Data will be stored on secure computers at Chelsea and Westminster Hospital using password protected 
access to databases.  
The data that is inserted into the prediction tool will be stored securely within a Microsoft excel 
database. Access will be granted using a single user log-in and password known only to the CI and PI. The 
database will be securely stored on a hospital computer within the unit in a locked area.  
Hard copy data (ICFs and registration forms) will be stored within the unit site files which will be kept in 
secure areas.  
12. ETHICAL AND REGULATORY CONSIDERATIONS 
12.1. 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki. 
12.2. 
ICH Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in full conformity with relevant regulations and 
with the ICH Guidelines for Good Clinical Practice. 
12.3. 
Approvals 
All relevant documentation will be submitted to the NHS Research Ethics Committee (REC), and host 
institution R&D departments. The Investigator will submit and, where necessary, obtain approval from 
the above parties for all substantial amendments to the original approved documents. 
12.4. 
Reporting 
An End of Study notification and final report will be submitted to the NHS REC and host R&D 
departments. The study is registered with clinicaltrials.gov and results will be submitted electronically.  
12.5. 
Participant Confidentiality 
The acquired data will be stored on a computer that is password protected. Data will be held in the NHS 
database of the host institution. Data will be kept for three years. 
All paperwork will be stored in a locked clinical office within the Department of Early Pregnancy and 
Acute Gynaecology of the host institution. 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 16 of 22 
A unique patient/volunteer identification number will be used to prevent identification of subjects 
involved in the study. 
13. FINANCE AND INSURANCE 
13.1. 
Funding 
No external funding is required. The CI is employed as a clinical research fellow at Chelsea and 
Westminster Hospital.  
13.2. 
Insurance 
Chelsea and Westminster Hospital NHS Foundation Trust has appropriate indemnity arrangements in 
place. 
14. PUBLICATION POLICY 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and 
any other publications arising from the study.  Authorship will be determined in accordance with the 
ICMJE guidelines and other contributors will be acknowledged. 
 
 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 17 of 22 
15. REFERENCES 
1) Bottomley C, Van Belle V, Mukri F et al. The optimal timing of an ultrasound scan to assess the 
location and viability of an early pregnancy. Hum Reprod. 2009 Aug;24(8):1811-7 
2) Davison AZ, Appiah A, Sana Y et al. (2014). The psychological effects and patient acceptability of 
a test to predict viability in early pregnancy: a prospective randomised study. Eur J Obstet 
Gynceol Reprod Biol. 178:95-99 
3) Richardson A, Raine-Fenning N, Deb S et al. (2016). Anxiety associated with diagnostic 
uncertainties in early pregnancy. Ultrasound Obstet Gynecol. Accepted Author Manuscript. 
Doi:10.1002/uog.17214 
4) Bottomley C, Van Belle V, Kirk E et al. (2013) Accurate prediction of pregnancy viability by means 
of a simple scoring system. Human Reproduction 28: 68–76 
5) Bottomley C, Van Belle V, Pexsters A et al. A model and scoring system to predict outcome of 
intrauterine pregnancies of uncertain viability. Ultrasound Obstet Gynecol 2011; 37: 588–595  
6) National Institute for Health and Care Excellence. Ectopic pregnancy and miscarriage: Diagnosis 
and Initial management in Early Pregnancy of Ectopic Pregnancy and miscarriage. NICE Clinical 
Guideline 154. London: NICE, 2012. 
7) Ingrid H. Lok, Richard Neugebauer, Psychological morbidity following miscarriage, Best Practice & 
Research Clinical Obstetrics & Gynaecology, Volume 21, Issue 2, 2007, Pages 229-247 
8) Farren J, Jalmbrant M, Ameye L, et al. Post-traumatic stress, anxiety and depression following 
miscarriage or ectopic pregnancy: a prospective cohort study. BMJ Open 2016;6:e011864. doi: 
10.1136/bmjopen-2016-011864 
9) National Institute for Health and Care Excellence. Ectopic pregnancy and miscarriage: A summary 
of selected new evidence relevant to NICE clinical guideline 154 ‘Diagnosis and initial 
management in early pregnancy of ectopic pregnancy and miscarriage’ (2012). Evidence Update 
71. London: NICE, December 2014 
10) Guha S, Van Belle V, Bottomley C et al. External validation of models and simple scoring systems 
to predict miscarriage in intrauterine pregnancies of uncertain viability. Hum Reprod. 2013 
Nov;28(11):2905-11. doi: 10.1093/humrep/det342. Epub 2013 Aug 26. 
11) Muller M, Bleker O, Bonsel G et al. Nuchal translucency screening and anxiety levels in pregnancy 
and puerperium. Ultrasound Obstet Gynecol 2006; 27: 357–361  
12) Van den Berg M, Dancet E, Erlikh T et al. Patient-centered early pregnancy care: a systematic 
review of quantitative and qualitative studies on the perspectives of women and their partners. 
Human Reproduction Update, Vol.24, No.1 pp. 106–118, 2018  
13) Moscrop A, Harrison S, Heppell V et al. Primary care follow-up and measured mental health 
outcomes among women referred for ultrasound assessment of pain and/or bleeding in early 
pregnancy: a quantitative questionnaire study. BMJ Open 2013;3: e002595. doi:10.1136/ 
bmjopen-2013-002595  

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 18 of 22 
14) Davis FD, Bagozzi RP, Warshaw PR. User acceptance of computer technology: a comparison of 
two theoretical models. Manage Sci. 1989;35:982–1002 
 
16. APPENDIX 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 19 of 22 
Appendix 1: Hospital Anxiety and Depression Score, Zigmond and Snaith 1983
 
 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 20 of 22 
Appendix 2: Patient Experience Questionnaire, modified from Davis et al 1989 
IMPROVE study 
PATIENT EXPERIENCE OF USING THE PREDICTION TOOL 
 
Thank you for taking the time to complete this short questionnaire regarding your experience of 
receiving the predicted outcome of your pregnancy, as part of the IMPROVE trial.  
 
We feel it is important to measure your experience to determine if the tool is both acceptable and useful 
to you during this difficult time.   
 
 
Satisfaction with medical care 
1) I am satisfied with the medical care that I have received overall 
 
1 
2 
3 
4 
5 
6 
7 
(please circle) 
strongly disagree  
 
 
 
    strongly agree 
 
Health Knowledge Scale  
2) I have a good understanding of my current diagnosis  
 
1 
2 
3 
4 
5 
6 
7 
(please circle) 
strongly disagree  
 
 
 
    strongly agree 
 
Information seeking preference  
3) I am someone who will always want to find out more information about a diagnosis using 
resources such as the internet  
 
1 
2 
3 
4 
5 
6 
7 
(please circle) 
strongly disagree  
 
 
 
    strongly agree 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 21 of 22 
 
4) I have used “Google” or other internet sites to search for “intrauterine pregnancy of uncertain 
viability” following my initial scan  
 
1 
2 
3 
4 
5 
6 
7 
(please circle) 
strongly disagree  
 
 
 
    strongly agree 
 
Please state which internet sites were used…………………………………………………………………………. 
…………………………………………………………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………………… 
 
5) I found these sites to be useful 
 
1 
2 
3 
4 
5 
6 
7 
(please circle) 
strongly disagree  
 
 
 
    strongly agree 
 
Perceived Usefulness   
6) The prediction tool has helped me better manage my expectations for my pregnancy 
 
1 
2 
3 
4 
5 
6 
7 
(please circle) 
strongly disagree  
 
 
 
    strongly agree 
 
7) I believe the prediction tool result is correct 
 
1 
2 
3 
4 
5 
6 
7 
(please circle) 
strongly disagree  
 
 
 
    strongly agree 
 
8) If offered I would use the prediction tool again in any future pregnancies diagnosed as IPUV 
 
1 
2 
3 
4 
5 
6 
7 
(please circle) 
strongly disagree  
 
 
 
    strongly agree 
 

 
 
 
 
IMPROVE Protocol February 2018, V3.0 
IRAS ID: 232277 
 
        CONFIDENTIAL 
 
 
Page 22 of 22 
 
17. AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol 
Version 
No. 
Date 
issued 
Author(s) of changes 
Details of Changes made 
1 
2.0 
November 
2017 
Kim Lawson  
Minor wording changes 
made  
2 
3.0 
January 
2018 
Kim Lawson 
Major changes made to 
study design