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Short title

Tommy's Graded Model pilot

Aim

The aim of this study is to evaluate the graded model of care for miscarriage with regards to feasibility, acceptability (to service users and providers), clinical and service use outcomes, implications on other services, and cost.

Trial Design

Pilot study

Setting

The implementation work would be piloted at the Birmingham Women’s Hospital (BWH) over a three-month period. Following the pilot, to ensure generalisability across geographically distinct regions of the UK, this miscarriage care package will also be implemented and evaluated in up to eight other NHS trusts.

Number of Participants

367 participants

Eligibility Criteria

Inclusion Criteria

All women who have miscarried pregnancies up to 14 weeks are eligible for care according to the graded model.

Exclusion Criteria

Molar pregnancy, ectopic pregnancy or a miscarriage at later gestations (> 14 weeks) will be excluded from the model as the aetiology and therefore management is different to first trimester miscarriage.

Study Interventions

Pilot of the graded model of care for miscarriage.

Duration of Study

3 month pilot

Outcome Measures

Service evaluation outcomes and data capture methods are detailed as follows:

Feasibility measures

• Demand - measured by the number of women receiving care as per the graded model and semi-structured interviews (SSI) – recruitment and retention (percentage of women receiving care (the denominator is women diagnosed with miscarriage in the EPAU, proportion of women lost to follow-up or declining referral to services) and thematic analysis
• Delivery - adherence and adaptations assessed by direct observation of practice (DOP), random case note review, completion of an implementation checklist and SSI – analysis of proportion and thematic analysis
• Adoption - setting level (proportion of patients approached that participate) and staff level (SSI to understand staff participation) – percentage of patients approached that participate and thematic analysis
• Fidelity - completed referrals to services or for further tests (e.g. full blood counts and thyroid function tests or scans) – n is the total number of indicated referrals, tests, or scans
• Practicality - time taken to complete consultation – comparison with time taken for consultations prior to implementation; thematic analysis and SSI
• Experience - barriers, facilitators, feasibility assessment on Likert scale assessed by SSI with key stakeholders and focus group discussions with EPAU staff – thematic analysis and analysis of Likert scale
• Sustainability - continuation of service following implementation assessed by direct observation of practice, random case note review –analysis of the proportion of women receiving care as per the graded model compared with the total number of women diagnosed with miscarriage in EPAU

Acceptability to service user

• Confidence in service - ‘How confident are you that if you required treatment this model of care would be able to support you?’, ranging from ‘not at all confident’ to ‘completely confident’ – analysis of Visual analogue scores
• Experience - experience and burden assessed using SSI, friends and family survey– thematic analysis, analysis of results of friends and family survey
• Negative consequences - burden and knock on effects assessed during SSI and any complaints through Patient advice and liaison service (PALS) – thematic analysis
• Appropriateness - perceived appropriateness assessed using SSI – thematic analysis
• Satisfaction - retrospective client satisfaction questionnaire (CSQ-8) – Mixed methods (scores of overall experiences and CSQ-8 and themes through SSI)

Acceptability to providers

• Experience - experience assessed using SSI with key stakeholders and focus group discussions – thematic analysis
• Negative consequences - burden and knock on effects assessed during SSI – thematic analysis
• Appropriateness - perceived appropriateness assessed using SSI – thematic analysis

Clinical outcomes: modifiable risk factors

• Proportion of women who are smokers
• Proportion of women who are underweight, overweight and obese
• Proportion of women with underlying medical conditions
• Proportion of women with abnormal thyroid function tests

Clinical outcomes

• Miscarriages averted
• Additional live births
• Women identified to be at risk of obstetric adverse events (preterm birth, intra-uterine growth restriction, Stillbirth)
• Women identified to be at risk of perinatal mental health consequences

Service use outcomes

• Number of referrals to specialist services (e.g. smoking cessation)
• Number of declined referrals
• Number of women who had previously been referred to services
• Number of appointments
• Type of appointment (face-to-face or telephone)
• Time taken for each appointment
• Number of full blood counts performed and proportion of abnormal tests requiring further intervention
• Number of thyroid function tests performed and proportion of abnormal tests requiring further intervention
• Number of declined full blood counts
• Number of declined thyroid function tests
• Number of reassurance scans
• Number of declined reassurance scans
• Number of cases where care did not follow the graded model of care package
• Time taken (days) until first appointment with the graded model care service

Implications on other services

• Service use - data collection on rates of referrals to services in the baseline and after implementation
• Negative consequences - burden and knock on effects assessed during SSI with other providers – thematic analysis

Implications of access to services

• Reach - data collection of sociodemographic characteristics of women accepting referrals to those women who declined – comparison of data and subgroup analysis
• Acceptability across different ethnicities - SSI with an ethnically diverse sample – thematic analysis
• Patient ease of participating - facilitators and barriers identified during SSI – thematic analysis

Health Economic Analysis

The primary objective of the economic evaluation within the pilot is to ascertain the cost-effectiveness of the graded model. Associated costs and health outcomes will be assessed for 367 patients. The core health outcome for this economic assessment is the quality-adjusted life year, which blends the duration and health-related quality of life achieved post-treatment. This will be measured using EQ-5D-5L utility scores, ensuring a robust evaluation of the graded model's effectiveness. The valuation of these outcomes will rely on the EQ-5D-5L health questionnaire, with utility values being drawn in line with NICE's recommended methods. Downstream resource use associated with the graded model will be obtained through SF-12, iMTA productivity cost questionnaire and bespoke questionnaires given to patients.

The ultimate of this pilot is to compare the clinical and cost implications of the graded model against the existing standard of care, utilising a vast dataset of UK healthcare records.

Project Team

• CI: Arri Coomarasamy, University of Birmingham
• Senior Investigators: Adam Devall, University of Birmingham and Mr Justin Chu, Birmingham Women’s and Children’s NHS Foundation Trust
• National Coordinator: Dr Rosinder Kaur, Birmingham Women’s and Children’s NHS Foundation Trust
• Team Leader: Lee Priest, University of Birmingham
• Lead Statistician: Christina Easter University of Birmingham

UoB (REC) Number

ERN_1158-Sep2023

Contact Details

Bwc.tommysclinics@nhs.net

Rxk193@student.bham.ac.uk

Short title

CORE-10 measure of psychological distress after miscarriage.

Aim

This study aims to evaluate the diagnostic accuracy of the CORE-10 online questionnaire in identifying women who meet DSM-V diagnostic criteria for psychopathology.

Trial Design

Validation study

Setting

Hospital

Number of Participants

595 women

Eligibility Criteria

Inclusion Criteria

• Female
• Primiparous or multiparous
• Ability to provide written informed consent to take part in this study
• Age ≥ 18 years old
• Diagnosis of miscarriage ≤16+6 weeks (Singleton or multiple pregnancy) acquired from hospital records
• Recurrent or sporadic miscarriage

Exclusion Criteria

• Miscarriage ≥ 17 weeks
• Other types of early pregnancy loss (e.g. gestational trophoblastic disease or ectopic pregnancy) acquired from hospital records
• Termination of pregnancy
• Prior enrolment in this study

Study Interventions

CORE-10 self-report online questionnaire three months (+/- 7 days) following the diagnosis of miscarriage. Diagnostic interviews will be administered within 28 days of the completion of the CORE-10 online questionnaire by members of the research team who will be blind to the results of the CORE-10. Women will be given a choice of whether to be interviewed by telephone or video call at a convenient time and place for them.

Duration of Study

End date: 31 December 2025

Outcome Measures

Primary Aim:

This work package aims to evaluate the diagnosis accuracy of the CORE-10 online questionnaire in identifying women who meet DSM-V diagnostic criteria for psychopathology.

Project Team

• CI: Arri Coomarasamy, University of Birmingham
• Senior Investigator: Adam Devall, University of Birmingham
• National Coordinator: Dr Rosinder Kaur, Birmingham Women’s and Children’s NHS Foundation Trust
• Team Leader: Lee Priest, University of Birmingham
• Consultant Clinical Psychologist: Dr Camilla Rosan, University College London
• Lead Statistician: Christina Easter University of Birmingham

NRES (REC) Number

16/WM/0423

Contact Details

core-10@contacts.bham.ac.uk

Rxk193@student.bham.ac.uk

l.priest.1@bham.ac.uk

tommys@contacts.bham.ac.uk

A number of important adaptations of the maternal immune system occur during pregnancy and recurrent miscarriage has been associated with disruptions to these mechanisms.

In particular, recurrent miscarriage has been associated in human studies with an increased Th1/Th2 ratio, reduced T regulatory cells, increased Th17 cells, and increased peripheral natural killer cells. These findings, coupled with extensive evidence of their importance in animal models of pregnancy loss, have led to suggestions that in some women immunological factors may be the cause of miscarriage.

To date the studies have been exploratory, limited by small sample sizes, single centre recruitment, and heterogeneity of the assays utilised. Such deficiencies in the existing evidence mean that national guidelines do not currently support detailed immunological testing. However, patient and clinician demand has led to a rapid expansion in testing outside NHS settings, without a robust evidence base to aid interpretations of the findings.

Therefore we are conducting research to elucidate the role of immune testing in patients with recurrent miscarriages, and identify potential targets for immune therapy. Our investigations will enable us to ensure that couples seeking help with recurrent miscarriage are given correct advice regarding the significance or not of immunological tests and the implications of the results for their future prognosis.

Project team

• Project lead: Professor Alex Richter
• Professor Mark Drayson
• Dr Hoda Harb
• Professor Arri Coomarasamy

A missed miscarriage, also known as a missed abortion or a silent miscarriage, occurs when the baby dies, but the body does not recognise this and so the pregnancy sac (where the baby grows) stays inside the body. Women who have had a missed miscarriage often opt for medical management up to 13+6 weeks of pregnancy.

NICE currently recommends that a drug called misoprostol (a vaginal pessary (medication inserted into the vagina) or tablet that makes the womb contract) should be used in the medical treatment of miscarriage. However, there is evidence to suggest that combining this drug with mifepristone (an oral tablet that reduces pregnancy hormones) may be more effective in treating miscarriage. The aim of the MifeMiso trial is to find out whether treating women with mifepristone followed by misoprostol, is more effective than misoprostol alone at resolving missed miscarriage.

Project team

• Project lead: Dr Justin Chu
• Dr Adam Devall
• Professor Tracy Roberts
• Dr Laura Jones
• Professor Arri Coomarasamy

Contact details: mifemiso@trials.bham.ac.uk

Sometimes it is necessary for doctors to suggest surgical treatment for miscarriage. Unfortunately, this can be associated with various problems such as causing a hole in the womb, infection, scarring and bleeding. This can cause problems with periods and decrease the chances of getting pregnant in the future. One of the ways that may improve gynaecological services is to increase the number of procedures performed under direct vision using hysteroscopy (a camera test which looks inside the womb), with the aim of improving treatment success rates and reducing complications.

The aim of the SEE U trial is to assess whether viewing the inside of the womb, with an ultrasound scan, during the surgical management of miscarriage can help with the success of the procedure. The trial is also looking to see if performing the procedure in this way can reduce complications such as infection, bleeding and scarring. To answer this question a multi-centre randomised controlled study with an associated health economic evaluation is required. To ensure the feasibility of a large expensive trial it is essential to perform a pilot study. This pilot study will assess various aspects of the trial design and management and provide preliminary data that can be used to plan a substantive trial.

Project team

• Project lead: Dr Paul Smith
• Dr Adam Devall
• Professor Arri Coomarasamy

Contact details: seeu@trials.bham.ac.uk

Until now, miscarriage has generally been considered an exclusively female problem, with investigations and management targeting only women.

Yet the role of sperm DNA damage in miscarriage is not surprising. This is because while most cell types are able to repair damaged DNA, sperm lose this ability during development and have to rely on repair mechanisms in the egg. As the level of damage in the sperm DNA increases it also becomes increasingly likely that any repairs by the egg may create genetic mutations that could increase the risk of miscarriage.

Most existing tests for sperm DNA damage are insufficiently sensitive to be clinically useful; we are developing a more accurate combined assay system and therapies to achieve repair. One potential cause of sperm DNA damage is exposure to Reactive Oxygen Species (ROS) during production and transit. We are investigating the possibilities for changes in antioxidant balance to reduce the risk of miscarriage.

We are about to commence the pAToMiUM pilot trial to test the effects of a combined vitamin and mineral supplement in 30 men with poor sperm DNA quality in a recurrent miscarriage population. We have worked with one of Europe’s leading producers of nutritional supplements to design the supplement formulation according to the latest evidence.

Project team

• Project lead: Professor Jackson Kirkman-Brown
• Dr Sarah Conner
• Dr Justin Chu
• Dr Adam Devall
• Professor Arri Coomarasamy

Contact details: patomium@trials.bham.ac.uk

We aim to better understand the psychosocial effects of miscarriages, and to harness this understanding to enable early pregnancy doctors, midwives and nurses to improve miscarriage care and support.

In November 2017 the European Society of Human Reproduction and Embryology particularly observed that there is a need for studies of the emotional impact of recurrent pregnancy loss on men. Therefore, we are speaking to men who have recently lived through two or more pregnancies that both ended spontaneously before 16 completed weeks of gestation. We hope to learn from their stories and understand whether and how men who experience multiple miscarriages could be better supported. The results of our research will inform the ongoing efforts of clinical teams and charities to help any individuals and families who find themselves affected by multiple miscarriages.

The PROMISE trial published in NEJM in 2015 represented a paradigm shift in miscarriage trials in the UK.

Before this trial, miscarriage research was generally conducted by a few specialists in single centre studies. The trials were small and took many years to complete, and often there were questions about the generalisability of the findings. As the first ever miscarriage prevention trial to recruit more than 800 participants, PROMISE created a network of hospitals around the country that is committed and able to carry out miscarriage research.

The network is currently demonstrating its value and tenacity in other trials of thousands of couples experiencing pregnancy loss. It is supported by a broad group of stakeholders, including members of the Association of Early Pregnancy Units, the Early Pregnancy Clinical Studies Group, BCTU (the largest women’s health clinical trials unit nationwide) and various other key academic and clinical institutions across the UK.

We are working together to become a national platform to better identify miscarriage prevention and management strategies, and facilitate the development of our next generation of clinical trial researchers.

Project team

• Project lead: Dr Rima Dhillon-Smith
• Dr Justin Chu
• Dr Adam Devall
• Professor Arri Coomarasamy

We still don’t know enough about why some women experience multiple miscarriages. In addition, different hospitals have different standards of care for women who have had a miscarriage. For example, many couples will only be investigated after they have had three miscarriages. This system causes unimaginable, and unnecessary, pain for the women affected. Tommy’s Net is a database that will help us to collect and store information from hospitals and clinics, as well as access current medical records. This will allow the team to develop new methods to tell which women are at most risk of having a miscarriage.

We are also able to use this cohort of patients to test new treatments using a cohort multiple Randomised Controlled Trial (cmRCT) design. This is a relatively new trial design that simplifies the recruitment and conduct of trials compared with current RCTs. In this trial design, participants are asked to agree to participate in the control arm of any future trials that will be conducted by the research team.

Once a substantial cohort of participants has been established that have given their consent to participate in the cmRCT, one is able to conduct a trial by identifying and selecting a random sample of participants who will receive the intervention, and another group that will continue to receive standard care. Those patients that are allocated to the intervention will be invited to give their written, informed consent to participate in the intervention arm. However, those allocated to standard care (control arm), can continue to be followed up in the usual way with no additional contact required.

Relevant outcomes and other measures are taken on all patients in both arms as part of the regular follow-up process. A large benefit of this trial design is that the same cohort can be used for multiple interventions, so are large number of clinical trials can be conducted within the same core cohort of patients.

Project team

• Project lead: Dr Rima Dhillon-Smith
• Dr Adam Devall
• Professor Arri Coomarasamy

Contact details: bwh-tr.tommysclinic@nhs.net