Jane Elizabeth Norman

Background: Globally, caesarean births (CB), including emergency caesareans births (EmCB), are rising. It is estimated that nearly a third of all births will be CB by 2030.Objectives: Identify and summarise the results from studies developing and validating prognostic multivariable models predicting the risk of EmCBs. Ultimately understanding the accuracy of their development, and whether they are operationalised for use in routine clinical practice.Search Strategy: Studies were identified using databases: MEDLINE, CINAHL, Cochrane Central and Scopus with a search strategy tailored to models predicting EmCBs.Selection Criteria: Prospective studies developing and validating clinical prediction models, with two or more covariates, to predict risk of EmCB.Data Collection and Analysis: Data were extracted onto a proforma using the Prediction model Risk Of Bias ASsessment Tool (PROBAST).Results: In total, 8083 studies resulted in 56 unique prediction modelling studies and seven validating studies, with a total of 121 different predictors. Frequently occurring predictors included maternal height, maternal age, parity, BMI and gestational age. PROBAST highlighted 33 studies with low overall bias, and these all internally validated their model. Thirteen studies externally validated; only eight of these were graded an overall low risk of bias. Six models offered applications that could be readily used, but only one provided enough time to offer a planned caesarean birth (pCB). These well‐refined models have not been recalibrated since development. Only one model, developed in a relatively low‐risk population, with data collected a decade ago, remains useful at 36 weeks for arranging a pCB.Conclusion: To improve personalised clinical conversations, there is a pressing need for a model that accurately predicts the timely risk of an EmCB for women across diverse clinical backgrounds.Trial Registration: PROSPERO registration number: CRD42023384439.

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: Incidence of gestational diabetes mellitus (GDM) is increasing and is associated with adverse perinatal outcomes including macrosomia, pre-eclampsia, and pre-term delivery. Optimum glycaemic control can reduce these adverse perinatal outcomes. Continuous glucose monitoring (CGM) informs users about interstitial glucose levels allowing early detection of glycaemic excursions and pharmacological or behavioural intervention. Few adequately powered RCTs to evaluate the impact of using CGM in women with GDM on perinatal outcomes have been undertaken.We aim to establish the feasibility of a multi-site RCT to evaluate the clinical- and cost-effectiveness of an intermittently scanned continuous glucose monitor (isCGM) compared with self-monitored blood glucose (SMBG) in women with GDM for reducing fetal macrosomia and improving maternal and fetal outcomes. We will evaluate recruitment and retention rates, adherence to device requirements, adequacy of data capture and acceptability of trial design and isCGM devices.Methods: Open-label multicentre randomised controlled feasibility trial. Inclusion criteria: pregnant women, singleton pregnancy, recent diagnosis of GDM (within 14 days of commencing medication, up to 34 weeks gestation) prescribed metformin and/or insulin. Women will be consecutively recruited and randomised to isCGM (FreestyleLibre2) or SMBG. At every antenatal visit, glucose measurements will be evaluated. The SMBG group will use blinded isCGM for 14 days at baseline (~ 12–32 weeks) and ~ 34–36 weeks. The primary outcome is the recruitment rate and absolute number of women participating. Clinical assessments of maternal and fetal/infant health will be undertaken at baseline, birth, up to ~ 13 weeks post-natal. Psychological, behavioural and health economic measures will be assessed at baseline and ~ 34–36 weeks gestation. Qualitative interviews will be undertaken with study decliners, participants, and professionals to explore trial acceptability, of using isCGM and SMBG.Discussion: GDM can be associated with adverse pregnancy outcomes. isCGM could offer a timely, easy-to-engage-with intervention, to improve glycaemic control, potentially reducing adverse pregnancy, birth and long-term health outcomes for mother and child. This study will determine the feasibility of conducting a large-scale multisite RCT of isCGM in women with GDM.Trial registration: This study has been registered with the ISRCTN (reference:ISRCTN42125256, Date registered: 07/11/2022).

Background: Around 60,000 babies are born preterm (prior to 37 weeks' gestation) each year in the UK. There is little evidence on the optimal birth mode (vaginal or caesarean section). Objective: The overall aim of the CASSAVA project was to determine if a trial to define the optimal mode of preterm birth could be carried out and, if so, determine what sort of trial could be conducted and how it could best be performed. We aimed to determine the specific groups of preterm women and babies for whom there are uncertainties about the best planned mode of birth, and if there would be willingness to recruit to, and participate in, a randomised trial to address some, but not all, of these uncertainties. This project was conducted in response to a Heath Technology Assessment programme commissioning call (17/22 'Mode of delivery for preterm infants'). Methods: We conducted clinician and patient surveys (n = 224 and n = 379, respectively) to identify current practice and opinion, and a consensus survey and Delphi workshop (n = 76 and n = 22 participants, respectively) to inform the design of a hypothetical clinical trial. The protocol for this clinical trial/vignette was used in telephone interviews with clinicians (n = 24) and in focus groups with potential participants (n = 13). Results: Planned sample size and data saturation was achieved for all groups except for focus groups with participants, as this had to be curtailed because of the COVID-19 pandemic and data saturation was not achieved. There was broad agreement from parents and health-care professionals that a trial is needed. The clinician survey demonstrated a variety of practice and opinion. The parent survey suggested that women and their families generally preferred vaginal birth at later gestations and caesarean section for preterm infants. The interactive workshop and Delphi consensus process confirmed the need for more evidence (hence the case for a trial) and provided rich information on what a future trial should entail. It was agreed that any trial should address the areas with most uncertainty, including the management of women at 26-32 weeks' gestation, with either spontaneous preterm labour (cephalic presentation) or where preterm birth was medically indicated. Clear themes around the challenges inherent in conducting any trial emerged, including the concept of equipoise itself. Specific issues were as follows: different clinicians and participants would be in equipoise for each clinical scenario, effective conduct of the trial would require appropriate resources and expertise within the hospital conducting the trial, potential participants would welcome information on the trial well before the onset of labour and minority ethnic groups would require tailored approaches. Conclusion: Given the lack of evidence and the variation of practice and opinion in this area, and having listened to clinicians and potential participants, we conclude that a trial should be conducted and the outlined challenges resolved. Future work: The CASSAVA project could be used to inform the design of a randomised trial and indicates how such a trial could be carried out. Any future trial would benefit from a pilot with qualitative input and a study within a trial to inform optimal recruitment. Limitations: Certainty that a trial could be conducted can be determined only when it is attempted. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 61. See the NIHR Journals Library website for further project information.

Background: The diagnosis of preterm labour is challenging. False-positive diagnoses are common and result in unnecessary, potentially harmful treatments (e.g. tocolytics, antenatal corticosteroids and magnesium sulphate) and costly hospital admissions. Measurement of fetal fibronectin in vaginal fluid is a biochemical test that can indicate impending preterm birth. Objectives: To develop an externally validated prognostic model using quantitative fetal fibronectin concentration, in combination with clinical risk factors, for the prediction of spontaneous preterm birth and to assess its cost-effectiveness. Design: The study comprised (1) a qualitative study to establish the decisional needs of pregnant women and their caregivers, (2) an individual participant data meta-analysis of existing studies to develop a prognostic model for spontaneous preterm birth within 7 days in women with symptoms of preterm labour based on quantitative fetal fibronectin and clinical risk factors, (3) external validation of the prognostic model in a prospective cohort study across 26 UK centres, (4) a model-based economic evaluation comparing the prognostic model with qualitative fetal fibronectin, and quantitative fetal fibronectin with cervical length measurement, in terms of cost per QALY gained and (5) a qualitative assessment of the acceptability of quantitative fetal fibronectin. Data sources/setting: The model was developed using data from five European prospective cohort studies of quantitative fetal fibronectin. The UK prospective cohort study was carried out across 26 UK centres. Participants: Pregnant women at 22⁺⁰–34⁺⁶ weeks’ gestation with signs and symptoms of preterm labour. Health technology being assessed: Quantitative fetal fibronectin. Main outcome measures: Spontaneous preterm birth within 7 days. Results: The individual participant data meta-analysis included 1783 women and 139 events of spontaneous preterm birth within 7 days (event rate 7.8%). The prognostic model that was developed included quantitative fetal fibronectin, smoking, ethnicity, nulliparity and multiple pregnancy. The model was externally validated in a cohort of 2837 women, with 83 events of spontaneous preterm birth within 7 days (event rate 2.93%), an area under the curve of 0.89 (95% confidence interval 0.84 to 0.93), a calibration slope of 1.22 and a Nagelkerke R ² of 0.34. The economic analysis found that the prognostic model was cost-effective compared with using qualitative fetal fibronectin at a threshold for hospital admission and treatment of ≥ 2% risk of preterm birth within 7 days. Limitations: The outcome proportion (spontaneous preterm birth within 7 days of test) was 2.9% in the validation study. This is in line with other studies, but having slightly fewer than 100 events is a limitation in model validation. Conclusions: A prognostic model that included quantitative fetal fibronectin and clinical risk factors showed excellent performance in the prediction of spontaneous preterm birth within 7 days of test, was cost-effective and can be used to inform a decision support tool to help guide management decisions for women with threatened preterm labour. Future work: The prognostic model will be embedded in electronic maternity records and a mobile telephone application, enabling ongoing data collection for further refinement and validation of the model. Study registration: This study is registered as PROSPERO CRD42015027590 and Current Controlled Trials ISRCTN41598423. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 52. See the NIHR Journals Library website for further project information.

Background: Cervical cerclage is a recognised treatment to prevent late miscarriage and pre-term birth (PTB). Emergency cervical cerclage (ECC) for cervical dilatation with exposed unruptured membranes is less common and the potential benefits of cerclage are less certain. A randomised control trial is needed to accurately assess the effectiveness of ECC in preventing pregnancy loss compared to an expectant approach. Methods: C-STICH2 is a multicentre randomised controlled trial in which women presenting with cervical dilatation and unruptured exposed membranes at 16 + 0 to 27 + 6 weeks gestation are randomised to ECC or expectant management. Trial design includes 18 month internal pilot with embedded qualitative process evaluation, minimal data set and a within-trial health economic analysis. Inclusion criteria are ≥16 years, singleton pregnancy, exposed membranes at the external os, gestation 16 + 0–27 + 6 weeks, and informed consent. Exclusion criteria are contraindication to cerclage, cerclage in situ or previous cerclage in this pregnancy. Randomisation occurs via an online service in a 1:1 ratio, using a minimisation algorithm to reduce chance imbalances in key prognostic variables (site, gestation and dilatation). Primary outcome is pregnancy loss; a composite including miscarriage, termination of pregnancy and perinatal mortality defined as stillbirth and neonatal death in the first week of life. Secondary outcomes include all core outcomes for PTB. Two-year development outcomes will be assessed using general health and Parent Report of Children’s Abilities-Revised (PARCA-R) questionnaires. Intended sample size is 260 participants (130 each arm) based on 60% rate of pregnancy loss in the expectant management arm and 40% in the ECC arm, with 90% power and alpha 0.05. Analysis will be by intention-to-treat. Discussion: To date there has been one small trial of ECC in 23 participants which included twin and singleton pregnancies. This small trial along with the largest observational study (n = 161) found ECC to prolong pregnancy duration and reduce deliveries before 34 weeks gestation. It is important to generate high quality evidence on the effectiveness of ECC in preventing pregnancy loss, and improve understanding of the prevalence of the condition and frequency of complications associated with ECC. An adequately powered RCT will provide the highest quality evidence regarding optimum care for these women and their babies. Trial registration: ISRCTN Registry ISRCTN12981869. Registered on 13th June 2018.

Background: Timely interventions in women presenting with preterm labour can substantially improve health outcomes for preterm babies. However, establishing such a diagnosis is very challenging, as signs and symptoms of preterm labour are common and can be nonspecific. We aimed to develop and externally validate a risk prediction model using concentration of vaginal fluid fetal fibronectin (quantitative fFN), in combination with clinical risk factors, for the prediction of spontaneous preterm birth and assessed its cost-effectiveness. Methods and findings: Pregnant women included in the analyses were 22⁺⁰ to 34⁺⁶ weeks gestation with signs and symptoms of preterm labour. The primary outcome was spontaneous preterm birth within 7 days of quantitative fFN test. The risk prediction model was developed and internally validated in an individual participant data (IPD) meta-analysis of 5 European prospective cohort studies (2009 to 2016; 1,783 women; mean age 29.7 years; median BMI 24.8 kg/m²; 67.6% White; 11.7% smokers; 51.8% nulliparous; 10.4% with multiple pregnancy; 139 [7.8%] with spontaneous preterm birth within 7 days). The model was then externally validated in a prospective cohort study in 26 United Kingdom centres (2016 to 2018; 2,924 women; mean age 28.2 years; median BMI 25.4 kg/m²; 88.2% White; 21% smokers; 35.2% nulliparous; 3.5% with multiple pregnancy; 85 [2.9%] with spontaneous preterm birth within 7 days). The developed risk prediction model for spontaneous preterm birth within 7 days included quantitative fFN, current smoking, not White ethnicity, nulliparity, and multiple pregnancy. After internal validation, the optimism adjusted area under the curve was 0.89 (95% CI 0.86 to 0.92), and the optimism adjusted Nagelkerke R² was 35% (95% CI 33% to 37%). On external validation in the prospective UK cohort population, the area under the curve was 0.89 (95% CI 0.84 to 0.94), and Nagelkerke R² of 36% (95% CI: 34% to 38%). Recalibration of the model’s intercept was required to ensure overall calibration-in-the-large. A calibration curve suggested close agreement between predicted and observed risks in the range of predictions 0% to 10%, but some miscalibration (underprediction) at higher risks (slope 1.24 (95% CI 1.23 to 1.26)). Despite any miscalibration, the net benefit of the model was higher than “treat all” or “treat none” strategies for thresholds up to about 15% risk. The economic analysis found the prognostic model was cost effective, compared to using qualitative fFN, at a threshold for hospital admission and treatment of ≥2% risk of preterm birth within 7 days. Study limitations include the limited number of participants who are not White and levels of missing data for certain variables in the development dataset. Conclusions: In this study, we found that a risk prediction model including vaginal fFN concentration and clinical risk factors showed promising performance in the prediction of spontaneous preterm birth within 7 days of test and has potential to inform management decisions for women with threatened preterm labour. Further evaluation of the risk prediction model in clinical practice is required to determine whether the risk prediction model improves clinical outcomes if used in practice. Trial registration: The study was approved by the West of Scotland Research Ethics Committee (16/WS/0068). The study was registered with ISRCTN Registry (ISRCTN 41598423) and NIHR Portfolio (CPMS: 31277).

Background: Preterm birth is common in twins and accounts for significant mortality and morbidity. There are no effective preventative treatments. Some studies have suggested that, in twin pregnancy complicated by a short cervix, the Arabin pessary, which fits around the cervix and can be inserted as an outpatient procedure, reduces preterm birth and prevents neonatal morbidity. Objective: STOPPIT 2 aimed to evaluate the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix. Design: STOPPIT 2 was a pragmatic, open label, multicentre randomised controlled trial with two treatment group – the Arabin pessary plus standard care (intervention) and standard care alone (control). Participants were initially recruited into the screening phase of the study, when cervical length was measured. Women with a measured cervical length of ≤ 35 mm were then recruited into the treatment phase of the study. An economic evaluation considered cost-effectiveness and a qualitative substudy explored the experiences of participants and clinicians. Setting: Antenatal clinics in the UK and elsewhere in Europe. Participants: Women with twin pregnancy at < 21 weeks’ gestation with known chorionicity and gestation established by scan at ≤ 16 weeks’ gestation. Interventions: Ultrasound scan to establish cervical length. Women with a cervical length of ≤ 35 mm at 18^+ 0–20^+ 6 weeks’ gestation were randomised to standard care or Arabin pessary plus standard care. Randomisation was performed by computer and accessed through a web-based browser. Main outcome measures: Obstetric – all births before 34^+ 0 weeks’ gestation following the spontaneous onset of labour; and neonatal – composite of adverse outcomes, including stillbirth or neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis or proven sepsis, all measured up to 28 days after the expected date of delivery. Results: A total of 2228 participants were recruited to the screening phase, of whom 2170 received a scan and 503 were randomised: 250 to Arabin pessary and 253 to standard care alone. The rate of the primary obstetric outcome was 18.4% (46/250) in the intervention group and 20.6% (52/253) in the control group (adjusted odds ratio 0.87, 95% confidence interval 0.55 to 1.38; p = 0.54). The rate of the primary neonatal outcome was 13.4% (67/500) and 15.0% (76/506) in the intervention group and control group, respectively (adjusted odds ratio 0.86, 95% confidence interval 0.54 to 1.36; p = 0.52). The pessary was largely well tolerated and clinicians found insertion and removal ‘easy’ or ‘fairly easy’ in the majority of instances. The simple costs analysis showed that pessary treatment is no more costly than standard care. Limitations: There was the possibility of a type II error around smaller than anticipated benefit. Conclusions: In this study, the Arabin pessary did not reduce preterm birth or adverse neonatal outcomes in women with a twin pregnancy and a short cervix. The pessary either is ineffective at reducing preterm birth or has an effect size of < 0.4. Future work: Women with twin pregnancy remain at risk of preterm birth; work is required to find treatments for this. Trial registration: Current Controlled Trials ISRCTN98835694 and ClinicalTrials.gov NCT02235181. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 44. See the NIHR Journals Library website for further project information.

Background. A negative association between obesity and pregnancy outcomes has been described, as well as between time sedentary and pregnancy outcomes. Most interventions based on physical activity involving obese pregnant women have failed in improving pregnancy outcomes. Exchanging time spent in sedentary activities with time spent in light-intensity activities, performed in a home-based setting, might help morbidly obese pregnant women. We aimed to assess the feasibility of an exercise intervention. Methods. An exercise intervention for morbidly obese pregnant women was designed involving morbidly obese pregnant women. Pregnant women with BMI ≥ 40 kg/m² with 20 or less weeks of gestation were invited to take part in the OPALS Feasibility Study. A home-based approach was employed. Participants were asked to perform the intervention for at least 12 weeks, and to register their performance in an activity diary. After the intervention, participants were asked to return the activity diary and answer a feasibility questionnaire. Results. In the intervention, 28 participants took part. Six women completed the intervention for 12 weeks or more. All declared they intended to keep on doing the intervention. All women reported that the exercises made them feel better. Conclusion. Empowering, and involving morbidly obese pregnant women in taking care of themselves and giving them realistic tasks to do on their own and around their environment helps to increase commitment, as does avoiding the effect of their own weight whilst exercising. A 20% of compliance was observed in this study, which might be explained by the difficulties that pregnancy and excess weight mean. Thus, for future studies, we suggest adding a supervision plan to increase that number.