Jane Daniels

Background We aimed to design and deliver a novel, ambitious perinatal platform to efficiently evaluate the clinical- and cost-effectiveness of multiple comparisons concurrently, recognising the inextricable link between pregnant women and babies. Methods We undertook extensive groundwork, holding discussions, focus groups, and conducting statistical simulations to explore and develop methodology to deliver a platform of trials. This included: 1. building sustainable partnerships across disciplines with expertise in the delivery of perinatal and platform trials 2. developing governance processes for selection of comparisons by multi-stakeholder oversight 3. setting up all aspects of project delivery 4. developing the IT systems/framework for data collection processes/data flows 5. working with parents, women and national charities to ensure integral public involvement 6. exploring views of healthcare professionals about the design/conduct of a perinatal platform trial 7. developing/refining required methodologies Results The main output from the accelerator award was a Stage 1 application to NIHR for a perinatal platform trial. Unfortunately, our bid was unsuccessful. The breadth of the network and of the planned work presented many challenges. However, we showed that collaboration across several clinical trials units/institutions is possible. Conclusions As long as institutions and individual researchers are primarily judged by research income, competition inevitably makes such endeavours complicated. Governance and legal aspects have yet to evolve sufficiently to reassure host institutions regarding risk management across multiple studies and institutions. It was imperative that our proposed platform allowed adaptations beyond adding or removing interventions. We created an agile infrastructure whereby new comparisons could be added. However, developing such an infrastructure that is futureproofed requires considerable upfront investment, which offsets many of the efficiencies that platform trials promise. None of these challenges were insurmountable. We have created a blueprint for the design and conduct of streamlined perinatal trials.

Background Vulval lichen sclerosus (LS) is a chronic inflammatory condition predominantly affecting female anogenital skin. It causes distressing symptoms that impact on daily living/quality of life (QOL), as well as causing progressive anatomical changes and increased cancer risk. First-line treatment with a very strong topical corticosteroid (TCS) brings LS into remission in around 70%. It is unclear how best to treat LS long-term. The PEARLS trial (ProactivE Against Reactive treatment for Lichen Sclerosus) will answer the research question : In people ≥5 years old with vulval LS, is maintenance treatment with a TCS twice weekly (‘proactive therapy’) better than as required treatment (‘reactive therapy’) for reducing number of flares over 12-months?

Lay summary: Endometriosis is a chronic pain condition that affects >190 million people worldwide. It is recommended in clinical guidelines to remove the most common type of endometriosis, ‘superficial peritoneal endometriosis’ (SPE), if it is diagnosed at laparoscopy (keyhole surgery). However, the evidence to support removal of SPE is based on small studies with short-term follow-up. The aim of this small feasibility trial was to determine what proportion of women with pelvic pain undergoing laparoscopy for suspected endometriosis would be willing to be randomly allocated to have surgical removal of SPE or not have it treated surgically straightaway (sham surgery). Of the eligible patients that were approached, 31% consented to take part, demonstrating that people with endometriosis are willing to take part in a sham surgical trial. We are now leading a similar, but much larger UK-wide trial, to determine whether removal of SPE truly improves painful endometriosis symptoms.

Background: Indwelling urinary catheters are drainage devices inserted into the bladder and are held in place by an inflatable balloon. The use of urinary catheters, while essential to bladder management, places the user at risk of catheter-associated urinary tract infections. Prevention of such infections in long-term catheter users could improve quality of life, and antimicrobial catheters may be more cost-effective compared with current plain catheters. We have developed and extensively characterised an indwelling antimicrobial urinary catheter impregnated with rifampicin, sparfloxacin and triclosan. We aimed to assess the effect of the antimicrobial urinary catheter on the number of catheter-associated urinary tract infections, blockages, unscheduled catheter changes, quality of life and resource use compared to usual care, over a 1-year period. We also aimed to assess the relative long-term safety, acceptability and cost-effectiveness of the novel catheter compared to current practice. Methods: Before the clinical trial could be undertaken, the antimicrobial catheters had to be manufactured and validated by an industry partner in a multistage process. Validation included impregnation, accelerated ageing and biocompatibility testing. Progress and challenges: Extensive device testing methods were developed and validated, including methods for determining the antimicrobial content of the catheters, detection of residual solvents and for an accelerated ageing process. A randomised clinical trial protocol was developed in parallel, in conjunction with patient advocates. A Trial Steering Committee was convened and a network of urology clinics created. The most significant challenge was that the industry partner was unable to consistently manufacture antimicrobial urinary catheters to the product specification. Much closer oversight of manufacturers processing the catheters is necessary to ensure compliance with protocols. The regulatory requirements for the novel catheters were also more extensive than anticipated and are subject to change. Delays accrued from these challenges, and there was uncertainty around the ability of the industry partner to produce a catheter. Ultimately, the project funder withdrew the funding before the clinical trial commenced. Conclusion: Catheter-associated urinary tract infections remain a serious problem, especially to long-term urinary catheter users, and there is currently no effective prophylactic strategy. Protocols for validation of impregnation and sterilisation steps for biocompatibility testing and accelerated ageing studies have been established and can be applied to future manufacture of antimicrobial urinary catheters. A protocol for a randomised trial of such medical device has been developed and can be deployed once a antimicrobial urinary catheter has been correctly manufactured. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme as award number NIHR127982.

Objective: To investigate the factors associated with non‐vasomotor menopause symptoms among women in the UK, focusing on the perceived importance of specific symptoms and their association with demographic and treatment‐related factors.Design: A cross‐sectional online survey.Setting: UK‐wide national survey conducted from February to March 2023.Population or Sample: A total of 7285 women completed the survey.Methods: Participants provided anonymised demographic data and rated the importance of five menopause symptoms (‘low mood’, ‘brain fog’, ‘aches and pains’, ‘feeling tired’, and ‘weight gain’) using a 10‐point Likert scale. The full questionnaire is provided in . Univariable and multivariable linear regression analyses were performed to assess the association between symptom importance scores and specific characteristics, including age, HRT and non‐HRT treatment, ethnicity, and geographical location.Main Outcome Measures: Importance scores of menopause symptoms stratified by demographic and treatment factors.Results: Significant differences were identified in perceived symptom importance across age groups, geographic locations, ethnic backgrounds, and treatment status. Brain fog was the most frequently prioritised symptom overall. Several moderate‐strength associations were observed: for example, HRT use was associated with higher importance ratings for brain fog, tiredness, low mood, and aches and pains. Ethnic minority women (Asian and Black) also gave higher importance ratings to brain fog.Conclusions: The findings highlight the prominence of cognitive and psychological symptoms during menopause and the influence of demographic and treatment variables on symptom prioritisation. These results support the need for personalised and inclusive menopause care that addresses a wider range of symptom concerns beyond vasomotor issues. These findings have implications for public health policy and financial investment.

Objectives To evaluate the cost-effectiveness of long-acting progestogens (LAP), including levonorgestrel-releasing intrauterine system (LNG-IUS) and depot-medroxyprogesterone acetate (DMPA), compared with the combined oral contraceptives pill (COCP) in preventing recurrence of endometriosis-related pain postsurgery. Design Within-trial economic evaluation alongside a multicentre, pragmatic, parallel-group, open-label, randomised controlled trial (Preventing Recurrence of Endometriosis by means of Long-Acting Progestogen Therapy trial). Setting Thirty-four UK hospitals recruiting participants from November 2015 to March 2019. Patients Four hundred and five women aged 16–45 years undergoing conservative endometriosis surgery. Interventions The ratio of 1:1 randomisation to receive LAPs (LNG-IUS or DMPA) or COCP. Main outcome measures The primary evaluation was a cost-utility analysis based on cost per quality-adjusted life-year (QALY) gained at 3 years. We adopted a UK National Health Service perspective. Secondary analyses in the form of cost-effectiveness analysis based on a range of outcomes were also undertaken. Results For the primary analysis, the COCP group incurred an additional cost of £533 (95% CI £52 to £983) per woman compared with LAPs. Treatment with COCP generated additional QALYs of 0.031 (95% CI −0.079 to 0.139) compared with the LAP group over 36-month follow-up. The incremental cost-effectiveness ratio for COCP compared with LAPs is therefore approximately £17 193 per QALY. The probabilistic sensitivity analysis suggested that there was a 54.7% probability that COCP would be cost-effective at the £20 000/QALY threshold. The secondary analyses revealed results more in favour of LAPs. Conclusion Although the COCP has a slightly higher probability of being cost-effective at £20 000/QALY threshold, there remains considerable uncertainty, with only marginal differences in outcomes between the two treatments. The lower rates of further surgery and second-line medical treatment for women allocated to LAPs may make this option preferable for some women. Trial registration number ISRCTN 97865475.

Background: Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Recurrence of symptoms following an operation is common. Although hormonal treatment can reduce this risk, there is uncertainty about the best option. Objectives: To evaluate the clinical and cost-effectiveness of long-acting progestogen therapy compared with the combined oral contraceptive pill in preventing recurrence of endometriosis-related pain and quality of life. Design: A multicentre, open, randomised trial with parallel economic evaluation. The final design was informed by a pilot study, qualitative exploration of women’s lived experience of endometriosis and a pretrial economic model. Setting: Thirty-four United Kingdom hospitals. Participants: Women of reproductive age undergoing conservative surgery for endometriosis. Interventions: Long-acting progestogen reversible contraceptive (either 150 mg depot medroxyprogesterone acetate or 52 mg levonorgestrel-releasing intrauterine system) or combined oral contraceptive pill (30 µg ethinylestradiol, 150 µg levonorgestrel). Main outcome measures: The primary outcome was the pain domain of the Endometriosis Health Profile-30 questionnaire at 36 months post randomisation. The economic evaluation estimated the cost per quality-adjusted life-years gained. Results: Four hundred and five women were randomised to receive either long-acting reversible contraceptive (N = 205) or combined oral contraceptive pill (N = 200). Pain scores improved in both groups (24 and 23 points on average) compared with preoperative values but there was no difference between the two (adjusted mean difference: −0.8, 95% confidence interval −5.7 to 4.2; p = 0.76). The long-acting reversible contraceptive group underwent fewer surgical procedures or second-line treatments compared with the combined oral contraceptive group (73 vs. 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). The mean adjusted quality-adjusted life-year difference between two arms was 0.043 (95% confidence interval −0.069 to 0.152) in favour of the combined oral contraceptive pill, although this cost an additional £533 (95% confidence interval 52 to 983) per woman. Limitations: Limitations include the absence of a no-treatment group and the fact that many women changed treatments over the 3 years of follow-up. Use of telephone follow-up to collect primary outcome data in those who failed to return questionnaires resulted in missing data for secondary outcomes. The COVID pandemic may have affected rates of further surgical treatment. Conclusions: At 36 months, women allocated to either intervention had comparable levels of pain, with both groups showing around a 40% improvement from presurgical levels. Although the combined oral contraceptive was cost-effective at a threshold of £20,000 per quality-adjusted life-year, the difference between the two was marginal and lower rates of repeat surgery might make long-acting reversible contraceptives preferable to some women. Future work: Future research needs to focus on evaluating newer hormonal preparations, a more holistic approach to symptom suppression and identification of biomarkers to diagnose endometriosis and its recurrence. Trial registration: This trial is registered as ISRCTN97865475. https://doi.org/10.1186/ISRCTN97865475. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/114/01) and is published in full in Health Technology Assessment; Vol. 28, No. 55. See the NIHR Funding and Awards website for further award information. The NIHR recognises that people have diverse gender identities, and in this report, the word ‘woman’ is used to describe patients or individuals whose sex assigned at birth was female, whether they identify as female, male or non-binary.

Background: Second trimester miscarriage and preterm birth is a significant global problem. Surgical cervical cerclage is performed to prevent pregnancy loss and preterm birth. It utilises either a monofilament or braided suture. It is hypothesised that a braided material becomes colonised with pathogenic bacteria that causes vaginal dysbiosis, infection and cerclage failure. Objectives: The primary objective of the study was to examine the effectiveness of using a monofilament suture material as opposed to a braided suture material on pregnancy loss in women requiring a vaginal cervical cerclage. Design: Superiority open randomised controlled trial. Setting: Seventy-five maternity sites across the UK. Participants: Women experiencing a singleton pregnancy requiring a cervical cerclage. Interventions: Monofilament suture or braided suture. Main outcome measures: The primary outcome was pregnancy loss (miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life). Secondary outcomes included the core outcome set for preterm birth. Methods: Women were randomised on a 1 : 1 basis to monofilament or braided cerclage utilising a bespoke randomisation service with minimisation dependent on the site, indication for cerclage, intention to use progesterone and planned surgical technique. The inclusion criteria were three or more previous mid-trimester losses or preterm births, insertion of a cerclage in a previous pregnancy, a history of a mid-trimester loss or preterm birth with a shortened cervical length in the current pregnancy or in women who clinicians deemed at risk of preterm birth. The exclusion criteria were an emergency or rescue cerclage, age of < 18 years, being unable to give informed consent or the cerclage having to be placed abdominally. The original sample size was calculated based on a relative risk reduction of 41% from a pregnancy loss rate of 19% in the braided group to 11% in the monofilament group with 90% power and alpha at p = 0.05. The independent data monitoring committee noted a lower-than-anticipated pooled event rate within the trial and recommended an increase in sample size to 2050. The outcome data were collected using clinical record forms from the maternal and neonatal medical records and reported to Birmingham Clinical Trials Unit. Results: A total of 2049 women were randomised, after withdrawals and loss to follow-up, data on 1005 women in the monofilament group and 993 women in the braided group were included. The baseline demographics between the groups were similar. There was no evidence of a difference in pregnancy loss rates between the monofilament and braided groups (80/1003 vs. 75/993; adjusted risk ratio: 1.05, 95% confidence interval: 0.79 to 1.40; adjusted risk difference: 0.002, 95% confidence interval: −0.02 to 0.03). Limitations: The trial did not collect long-term paediatric outcomes. There were no safety concerns. Conclusions: There was no evidence of a difference in pregnancy loss between a monofilament suture and a braided suture. Future work: Long-term follow-up of neonates born within the C-STICH (cerclage suture type for an insufficient cervix and its effects on health outcomes) trial. Trial registration: This trial is registered as ISRCTN15373349. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/04/107) and is published in full in Health Technology Assessment; Vol. 28, No. 40. See the NIHR Funding and Awards website for further award information.

Background: The risks and benefits of maternal screening for GBS during pregnancy or the intrapartum period are widely debated, since screen positive results trigger prophylactic antibiotic use. There is little known about women’s and health professional’s views regarding GBS screening. Objectives: To conduct a rapid review to synthesise evidence on women and health professionals’: (1) knowledge and awareness of; (2) preferences for; and (3) acceptability of GBS screening programmes, and (4) how feasible they are to implement. Method: Literature searches were conducted using online databases from their inception to 2023. Papers were included if they reported primary research from the perspectives of health professionals and women, about their knowledge and awareness, preferences, acceptability and feasibility of different types of GBS screening programmes. Data were assessed for confidence using GRADE- CERQual and analysed using a convergent synthesis approach. Findings: 42 papers were eligible for inclusion. A total of 16,306 women and professionals were included. Women generally did not have extensive knowledge about GBS. Health professionals had a higher level of knowledge than women. Women were generally (but not universally) positive about GBS testing procedures. Some women were concerned about the impact on their place of birth. Discussion and Conclusion: Where GBS screening programmes are available, parents must be provided with high quality information about them. Health professionals and service managers need to weigh up the benefits and risks of screening for GBS with local feasibility and treatment options, and with women’s individual values and birth plans. Statement of significance: Problem: Maternal GBS colonisation at birth can lead to invasive GBS disease. The risks and benefits of screening for GBS during pregnancy is widely debated. What is already known: Different countries use different GBS screening strategies, such as the universal screening strategy vs risk based. What this paper adds: The World Health Organization reviewed their GBS policy guidelines in 2024. Results from this paper were used to ensure women and health professional’s views were considered. This paper found that women are generally (but not universally) positive about GBS testing procedures with some concerned about the impact on their birth choices.