Fluidity of Equipoise in a Multi-Centred Pilot RCT:Influences on Clinician Decision-Making in Offering Trial Entry

Objectives: The embedded Qualitative Process Evaluation (QPE) within the CSTICH- Pilot RCT explored facilitators and barriers to recruitment within the Pilot. This study reports a secondary analysis of the overarching theme of Fluidity of Equipoise and the influences on individual and community clinical equipoise around the use of Emergency Cervical Cerclage (ECC). Study design: RCT recruitment assumes clinical equipoise and is defined as genuine uncertainty about an intervention. The ability of trial recruiters to convey this equipoise is also key to participant recruitment and fully informed consent. This exploratory qualitative process evaluation used semi-structured interviews with healthcare professionals (HCPs) involved in trial recruitment. Interviews were audio-recorded, transcribed, and analysed using codebook thematic analysis. Results: 23 HCPs were interviewed. Clinical equipoise around the use of ECC was variable and influenced by a multitude of factors including: (1) obstetric history; (2) gestation; (3) standard site practice, and (4) HCPs previous experiences of ECC. We have interpreted this variability as ‘fluidity of equipoise’. Conclusions: Clinical equipoise around complex pregnancy related conditions was fluid and influenced by the complexities of obstetric histories and gestation at presentation. Equipoise of HCPs involved in trial recruitment should be considered carefully as it can impact the nuances of recruitment, particularly in more challenging trials such as CSTICH-2. Study-specific documents and training can be used to increase staff and patient awareness of uncertainty in the evidence base for interventions under investigation. Further research is needed around the potential consequences of equipoise fluidity

The acceptability of emergency cervical cerclage within a randomised controlled trial for cervical dilatation with exposed membranes at 16–27 + 6 weeks gestation : findings from a qualitative process evaluation of the C-STICH2 pilot trial

Objective C-STICH2 is a randomised controlled trial of emergency cervical cerclage (ECC) vs routine care in women who present in pregnancy with premature cervical dilatation and exposed unruptured fetal membranes. Within the proposed trial an internal pilot was performed with an embedded qualitative process evaluation (QPE) to explore the feasibility of recruitment. The QPE aimed to collect and analyse data exploring the experiences of health care professionals (HCPs) involved in recruitment, and women approached about the trial. Methods Semi-structured interviews (telephone or face-to-face) were held with eligible participants who had consented to participate in the QPE. Interviews were audio-recorded, transcribed, and analysed to identify main themes. Interview transcripts were analysed using qualitative thematic analysis (QTA). Results 11 women and 23 HCPs were interviewed. Three super-ordinate themes of Fluidity of Equipoise, A Complex Obstetric History, and the Influence of Gestation were identified. Within these, the five main themes which influenced trial participation were: 1) Complex decision-making processes; 2) Predicting outcomes; 3) The importance of terminology and initial RCT approach; 4) Women’s understanding of the need for research in this area; 5) Changes in practice which are trial influenced. Conclusions For both HCPs and women and their families, there was a conflation of the potential risks and outcomes of ECC with those of elective cerclage and the complexity around ECC placement was not always well understood by those with less experience and understanding of the intervention. Decision making was shown to be complex and multi-factorial for both HCPs and women. For complex trials in rare conditions with treatment uncertainty, clinical equipoise is likely to be fluid and influenced by multiple factors

Radiofrequency thermal ablation of giant placental chorioangioma complicated with fetal hydrops: a case report and successful outcome

ObjectivesChorioangiomas are the most frequently occurring type of benign tumour of the placenta. However, large chorioangiomas greater than 4 cm are rare and can be more frequently associated with serious complications such as: polyhydramnios, hydrops fetalis, fetal anaemia, intrauterine growth restriction, preterm birth, and an increased risk of perinatal mortality. Importantly timely prenatal diagnosis with close surveillance alongside potential intrauterine intervention can prove impactful on pregnancy outcome and fetal survival.Case presentationWe present a case of a 36-year-old female referred to our tertiary fetal medicine unit at 28 weeks’ gestation with a large chorioangioma measuring 9.4×8.8×5.5 cm and ultrasonographic evidence of severe fetal anaemia and fetal hydrops. The patient underwent an intrauterine transfusion and in utero surgical therapy with radiofrequency ablation (RFA). Immediately following the procedure, the fetus sustained a period of bradycardia, followed by asystole. Delivery was expedited via emergency caesarean section. Careful planning and rapid delivery after fetal intervention within the most appropriate surgical setting mitigated risks for the baby and resulted in a positive outcome. The baby was discharged from the neonatal unit on day 84 of life.ConclusionsLarge placental chorioangiomas are a rare occurrence, however, when associated with fetal complications present a high incidence of adverse perinatal outcomes. In utero interventions require careful planning and surgical expertise to ensure improved fetal and neonatal outcomes. To the best of our knowledge this case is the first recorded instance of a successful postnatal outcome following RFA for a large placental chorioangioma, whereby the fetus was complicated by fetal hydrops

Prophylactic perioperative cefuroxime levels in plasma and adipose tissue at the time of caesarean section (C-LACE) : a protocol for a pilot experimental, prospective study with non-probability sampling to determine interpatient variability

Background: The aim of the C-LACE study is to measure cefuroxime concentration in plasma and adipose tissue of non-obese and obese pregnant women undergoing caesarean section. Methods: This study plans to compare maternal cefuroxime concentrations (plasma and adipose tissue), at the time of skin incision and time of skin closure during a caesarean section from non-obese (body mass index BMI < 30 kg/m2) and obese (BMI ≥ 30 kg/m2) pregnant women. The incidence of post-surgical site infection will also be measured. At least 15 participants are required for each arm (non-obese vs obese) with a total of 30 participants. The study participants will be followed up between 30 and 40 days post-caesarean section to record details of any post-caesarean surgical infection to explore correlations between BMI, measured cefuroxime concentrations and post-caesarean infection rates. Discussion: This pilot study will allow the development of a model testing the inter-patient variability in plasma and adipose tissue concentrations of cefuroxime. The results will facilitate the development of a larger study to determine whether differences in cefuroxime plasma and tissue concentration in obese and non-obese women can support the development of a physiologically based pharmacokinetic model. This model can then be used to propose dosing adjustments that can be used in a further trial to optimise cefuroxime dosing for women undergoing caesarean section. Trial registration: ISRCTN Registry, ISRCTN17527512. Registered on 26 October 202

Application of a physiologically based pharmacokinetic model to predict cefazolin and cefuroxime disposition in obese pregnant women undergoing caesarean section

Intravenous (IV) cefuroxime and cefazolin are used prophylactically in caesarean sections (CS). Currently, there are concerns regarding sub-optimal dosing in obese pregnant women compared to lean pregnant women prior to CS. The current study used a physiologically based pharmacokinetic (PBPK) approach to predict cefazolin and cefuroxime pharmacokinetics in obese pregnant women at the time of CS as well as the duration that these drug concentrations remain above a target concentration (2, 4 or 8 µg/mL or µg/g) in plasma or adipose tissue. Cefazolin and cefuroxime PBPK models were first built using clinical data in lean and in obese non−pregnant populations. Models were then used to predict cefazolin and cefuroxime pharmacokinetics data in lean and obese pregnant populations. Both cefazolin and cefuroxime models sufficiently described their total and free levels in the plasma and in the adipose interstitial fluid (ISF) in non−pregnant and pregnant populations. The obese pregnant cefazolin model predicted adipose exposure adequately at different reference time points and indicated that an IV dose of 2000 mg can maintain unbound plasma and adipose ISF concentration above 8 µg/mL for 3.5 h post dose. Predictions indicated that an IV 1500 mg cefuroxime dose can achieve unbound plasma and unbound ISF cefuroxime concentration of ≥8 µg/mL up to 2 h post dose in obese pregnant women. Re-dosing should be considered if CS was not completed within 2 h post cefuroxime administration for both lean or obese pregnant if cefuroxime concentrations of ≥8 µg/mL is required. A clinical study to measure cefuroxime adipose concentration in pregnant and obese pregnant women is warranted

C-STICH2: emergency cervical cerclage to prevent miscarriage and preterm birth—study protocol for a randomised controlled trial

Abstract 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

Trials and tribulations of trials in Obstetrics, evaluation of the randomised controlled trials of C-STICH, PREPS and C-STICH2

Introduction: An evaluation of trials in obstetrics. PREPS - Vaginal Preparation with chlorhexidine at Caesarean Section (CS) to Reduce Endometritis and Prevent Sepsis: feasibility RCT. C-STICH- Cerclage Suture Type for an Insufficient Cervix and its effect on Health outcomes. C-STICH2- RCT of emergency cervical cerclage vs expectant management in women with bulging membranes. Methods: PREPS –there were uncertainties regarding the ability to recruit (screen, consent and randomise) women undergoing emergency CS. Process were developed to overcome these challenges and tested within a feasibility RCT. C-STICH – an evaluation of the challenges of recruiting women undergoing a rare surgical procedure and managing a lower than anticipated control group event rate. C-STICH2 – to access the feasibility of recruitment when prognosis poor. Accessed via an RCT with internal pilot and embedded qualitative evaluation. Results: PREPS demonstrated it is feasible to perform an RCT of vaginal cleansing at CS to reduce SSI, using bespoke verbal consent and telephone randomisation. C-STICH demonstrated that by establishing a large clinical network you can recruit women undergoing a rare procedure. C-STICH 2 demonstrated the importance of including a mixed methods evaluation in trials when recruitment is challenging. Conclusion: New processes allow consent, randomisation and follow up in difficult trials

Aspirin use in pregnancy:where are we and what next?

Aspirin is currently recommended from 12 weeks gestation until the birth of the baby for women with one high, or two moderate risk factors for pre-eclampsia, to reduce the risk of developing the condition. There is evidence to suggest aspirin use in pregnancy potentially reduces the risk of preterm birth and small for gestational age or fetal growth restricted babies. For women with recurrent pregnancy loss associated with anti-phospholipid syndrome, aspirin is recommended in combination with heparin. In this review, we discuss the history of aspirin use and its application to improving pregnancy outcomes. We also highlight the current evidence surrounding aspirin use in pregnancy and explore avenues for further research

Aspirin use in pregnancy:where are we and what next?

Aspirin is currently recommended from 12 weeks gestation until the birth of the baby for women with one high, or two moderate risk factors for pre-eclampsia, to reduce the risk of developing the condition. There is evidence to suggest aspirin use in pregnancy potentially reduces the risk of preterm birth and small for gestational age or fetal growth restricted babies. For women with recurrent pregnancy loss associated with anti-phospholipid syndrome, aspirin is recommended in combination with heparin. In this review, we discuss the history of aspirin use and its application to improving pregnancy outcomes. We also highlight the current evidence surrounding aspirin use in pregnancy and explore avenues for further research