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.

Monofilament suture versus braided suture thread to improve pregnancy outcomes after vaginal cervical cerclage (C-STICH): a pragmatic randomised, controlled, phase 3, superiority trial.

BACKGROUND: Miscarriage in the second trimester and preterm birth are significant global problems. Vaginal cervical cerclage is performed to prevent pregnancy loss and preterm birth. We aimed to determine the effectiveness of a monofilament suture thread compared with braided suture thread on pregnancy loss rates in women undergoing a cervical cerclage. METHODS: C-STICH was a pragmatic, randomised, controlled, superiority trial done at 75 obstetric units in the UK. Women with a singleton pregnancy who received a vaginal cervical cerclage due to a history of pregnancy loss or premature birth, or if indicated by ultrasound, were centrally randomised (1:1) using minimisation to receive a monofilament suture or braided suture thread for their cervical cerclage. Women and outcome assessors were masked to allocation as far as possible. The primary outcome was pregnancy loss, defined as miscarriage, stillbirth, or neonatal death in the first week of life, analysed in the intention-to-treat population (ie, all women who were randomly assigned). Safety was also assessed in the intention-to-treat population. The trial was registered with ISRCTN, ISRCTN15373349. FINDINGS: Between Aug 21, 2015, and Jan 28, 2021, 2049 women were randomly assigned to receive a monofilament suture (n=1025) or braided suture (n=1024). The primary outcome was ascertained in 1003 women in the monofilament suture group and 993 women in the braided suture group. Pregnancy loss occurred in 80 (8·0%) of 1003 women in the monofilament suture group and 75 (7·6%) of 993 women in the braided suture group (adjusted risk ratio 1·05 [95% CI 0·79 to 1·40]; adjusted risk difference 0·002 [95% CI -0·02 to 0·03]). INTERPRETATION: Monofilament suture did not reduce rate of pregnancy loss when compared with a braided suture. Clinicians should use the results of this trial to facilitate discussions around the choice of suture thread to optimise outcomes. FUNDING: National Institute of Health Research Health Technology Assessment Programme.

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.

Tocolytics for delaying preterm birth: a network meta-analysis (0924).

BACKGROUND: Preterm birth is the leading cause of death in newborns and children. Tocolytic drugs aim to delay preterm birth by suppressing uterine contractions to allow time for administration of corticosteroids for fetal lung maturation, magnesium sulphate for neuroprotection, and transport to a facility with appropriate neonatal care facilities. However, there is still uncertainty about their effectiveness and safety. OBJECTIVES: To estimate relative effectiveness and safety profiles for different classes of tocolytic drugs for delaying preterm birth, and provide rankings of the available drugs. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov (21 April 2021) and reference lists of retrieved studies. SELECTION CRITERIA: We included all randomised controlled trials assessing effectiveness or adverse effects of tocolytic drugs for delaying preterm birth. We excluded quasi- and non-randomised trials. We evaluated all studies against predefined criteria to judge their trustworthiness. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed the trials for inclusion and risk of bias, and extracted data. We performed pairwise and network meta-analyses, to determine the relative effects and rankings of all available tocolytics. We used GRADE to rate the certainty of the network meta-analysis effect estimates for each tocolytic versus placebo or no treatment. MAIN RESULTS: This network meta-analysis includes 122 trials (13,697 women) involving six tocolytic classes, combinations of tocolytics, and placebo or no treatment. Most trials included women with threatened preterm birth, singleton pregnancy, from 24 to 34 weeks of gestation. We judged 25 (20%) studies to be at low risk of bias. Overall, certainty in the evidence varied. Relative effects from network meta-analysis suggested that all tocolytics are probably effective in delaying preterm birth compared with placebo or no tocolytic treatment. Betamimetics are possibly effective in delaying preterm birth by 48 hours (risk ratio (RR) 1.12, 95% confidence interval (CI) 1.05 to 1.20; low-certainty evidence), and 7 days (RR 1.14, 95% CI 1.03 to 1.25; low-certainty evidence). COX inhibitors are possibly effective in delaying preterm birth by 48 hours (RR 1.11, 95% CI 1.01 to 1.23; low-certainty evidence). Calcium channel blockers are possibly effective in delaying preterm birth by 48 hours (RR 1.16, 95% CI 1.07 to 1.24; low-certainty evidence), probably effective in delaying preterm birth by 7 days (RR 1.15, 95% CI 1.04 to 1.27; moderate-certainty evidence), and prolong pregnancy by 5 days (0.1 more to 9.2 more; high-certainty evidence). Magnesium sulphate is probably effective in delaying preterm birth by 48 hours (RR 1.12, 95% CI 1.02 to 1.23; moderate-certainty evidence). Oxytocin receptor antagonists are probably effective in delaying preterm birth by 48 hours (RR 1.13, 95% CI 1.05 to 1.22; moderate-certainty evidence), are effective in delaying preterm birth by 7 days (RR 1.18, 95% CI 1.07 to 1.30; high-certainty evidence), and possibly prolong pregnancy by 10 days (95% CI 2.3 more to 16.7 more). Nitric oxide donors are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.05 to 1.31; moderate-certainty evidence), and 7 days (RR 1.18, 95% CI 1.02 to 1.37; moderate-certainty evidence). Combinations of tocolytics are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.07 to 1.27; moderate-certainty evidence), and 7 days (RR 1.19, 95% CI 1.05 to 1.34; moderate-certainty evidence). Nitric oxide donors ranked highest for delaying preterm birth by 48 hours and 7 days, and delay in birth (continuous outcome), followed by calcium channel blockers, oxytocin receptor antagonists and combinations of tocolytics. Betamimetics (RR 14.4, 95% CI 6.11 to 34.1; moderate-certainty evidence), calcium channel blockers (RR 2.96, 95% CI 1.23 to 7.11; moderate-certainty evidence), magnesium sulphate (RR 3.90, 95% CI 1.09 to 13.93; moderate-certainty evidence) and combinations of tocolytics (RR 6.87, 95% CI 2.08 to 22.7; low-certainty evidence) are probably more likely to result in cessation of treatment. Calcium channel blockers possibly reduce the risk of neurodevelopmental morbidity (RR 0.51, 95% CI 0.30 to 0.85; low-certainty evidence), and respiratory morbidity (RR 0.68, 95% CI 0.53 to 0.88; low-certainty evidence), and result in fewer neonates with birthweight less than 2000 g (RR 0.49, 95% CI 0.28 to 0.87; low-certainty evidence). Nitric oxide donors possibly result in neonates with higher birthweight (mean difference (MD) 425.53 g more, 95% CI 224.32 more to 626.74 more; low-certainty evidence), fewer neonates with birthweight less than 2500 g (RR 0.40, 95% CI 0.24 to 0.69; low-certainty evidence), and more advanced gestational age (MD 1.35 weeks more, 95% CI 0.37 more to 2.32 more; low-certainty evidence). Combinations of tocolytics possibly result in fewer neonates with birthweight less than 2500 g (RR 0.74, 95% CI 0.59 to 0.93; low-certainty evidence). In terms of maternal adverse effects, betamimetics probably cause dyspnoea (RR 12.09, 95% CI 4.66 to 31.39; moderate-certainty evidence), palpitations (RR 7.39, 95% CI 3.83 to 14.24; moderate-certainty evidence), vomiting (RR 1.91, 95% CI 1.25 to 2.91; moderate-certainty evidence), possibly headache (RR 1.91, 95% CI 1.07 to 3.42; low-certainty evidence) and tachycardia (RR 3.01, 95% CI 1.17 to 7.71; low-certainty evidence) compared with placebo or no treatment. COX inhibitors possibly cause vomiting (RR 2.54, 95% CI 1.18 to 5.48; low-certainty evidence). Calcium channel blockers (RR 2.59, 95% CI 1.39 to 4.83; low-certainty evidence), and nitric oxide donors probably cause headache (RR 4.20, 95% CI 2.13 to 8.25; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Compared with placebo or no tocolytic treatment, all tocolytic drug classes that we assessed (betamimetics, calcium channel blockers, magnesium sulphate, oxytocin receptor antagonists, nitric oxide donors) and their combinations were probably or possibly effective in delaying preterm birth for 48 hours, and 7 days. Tocolytic drugs were associated with a range of adverse effects (from minor to potentially severe) compared with placebo or no tocolytic treatment, although betamimetics and combination tocolytics were more likely to result in cessation of treatment. The effects of tocolytic use on neonatal outcomes such as neonatal and perinatal mortality, and on safety outcomes such as maternal and neonatal infection were uncertain.

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.

Advanced dressings for the prevention of surgical site infection in women post-caesarean section: A systematic review and meta-analysis.

OBJECTIVE(S): Surgical site infections (SSIs) are a common complication post-caesarean section. Advanced dressings aim to provide an optimal wound environment, primarily by physically or chemically controlling moisture, in order to promote timely healing. A systematic review and meta-analysis was conducted to evaluate the effectiveness of advanced dressings in SSI prevention post-caesarean section. Secondary effectiveness outcomes included superficial SSI, endometritis, wound dehiscence, rehospitalisation and length of rehospitalisation. STUDY DESIGN: We conducted a systematic review and meta-analysis according to PRISMA guidelines. A protocol was registered a priori. MEDLINE, EMBASE, CENTRAL and CINAHL databases were searched from inception to May 2021, without date or language restrictions. Keywords included: caesarean section; bandages; dressing and surgical wound infection. Randomised controlled trials (RCTs) were included if they investigated any advanced dressing in women post-caesarean section compared to simple dressings and assessed SSI incidence. Relative risks (RR), with 95% confidence intervals (CIs) and p-values, were calculated using Review Manager software (RevMan version 5.0, The Cochrane Collaboration). I2 percentages were reported to assess heterogeneity and a funnel plot was produced to assess publication bias. Quality assessment was performed using the Cochrane Risk of Bias Assessment Tool. All data were double-extracted and discrepancies were finalised by a third reviewer. RESULTS: From 253 citations identified, six RCTs were included in the systematic review and meta-analysis. Two studies investigated dialkylcarbamoyl chloride (DACC)-impregnated dressings; two investigated silver-impregnated dressings; one investigated copper-impregnated dressings and one investigated chlorhexidine gluconate dressings. The overall meta-analysis showed that advanced dressings did not reduce SSI risk (RR 0.81 [95% CI 0.52-1.24; p = 0.32]). However, subgroup analysis revealed that DACC-impregnated dressings reduced SSI risk (RR 0.33 [95% CI 0.14-0.77; p = 0.01]). Silver-impregnated dressings caused a nonsignificant increase in SSI risk (RR 1.20 [95% CI 0.77-1.88; p = 0.41]). All studies showed a high risk of bias. CONCLUSION: This systematic review and meta-analysis suggests DACC dressings potentially reduce SSI. However we have shown no benefit of silver dressings. Further high-quality RCTs are required to recommend a change in clinical practice.

A prognostic model, including quantitative fetal fibronectin, to predict preterm labour: the QUIDS meta-analysis and prospective cohort study.

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 R2 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.

Identifying which women with symptoms of labour will give birth early is challenging, so many women unnecessarily receive therapies aimed at preventing complications in preterm birth. A test called quantitative fetal fibronectin, which uses vaginal swab samples, may help to improve the diagnosis of preterm labour. Fetal fibronectin is a protein that is released from the fetal membranes that surround the developing baby in the womb. The lower the concentration of fetal fibronectin, the less likely the occurrence of preterm birth. Our aim was to see if quantitative fetal fibronectin, in combination with some features of pregnancy (e.g. previous pregnancy history and twin pregnancy), can accurately predict preterm birth in women who have symptoms of preterm labour. We asked women, their partners, doctors and midwives what information would be most useful to them, and how this should be presented. We then analysed previous research data; we used quantitative fetal fibronectin and clinical risk factors together to predict the chance of preterm birth. We explored which features could predict preterm birth most effectively while still being good value to the NHS. To ensure that this risk predictor worked in UK populations, we undertook a research study across 26 UK hospitals. Women who had symptoms of preterm labour were invited to participate. We collected information from these women (approximately 3000 women), including quantitative fetal fibronectin results. We found that a risk predictor comprising quantitative fetal fibronectin and four other features performed best at predicting whether or not preterm birth will occur within the next week for women with symptoms of preterm labour, and that this had potential to be clinically useful and cost-effective. The quantitative fetal fibronectin testing process was acceptable to women, and clinicians found the risk predictor useful. We used our findings to develop a risk calculator to help women and clinicians assess how likely preterm birth is, and decide whether or not to start treatment.

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

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.

Development and validation of a risk prediction model of preterm birth for women with preterm labour symptoms (the QUIDS study): A prospective cohort study and individual participant data meta-analysis.

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).

Outcomes in intervention and management of multiple pregnancies trials: A systematic review.

OBJECTIVES: Twin pregnancy has risks of adverse outcomes for mother and baby. Data synthesis is required to gain evidence to aid recommendations but may be hampered by variations in outcome reporting. STUDY DESIGN: Systematically review outcomes reported in twin pregnancy trials (PROSPERO - CRD42019133805). Searches were performed in MEDLINE, EMBASE, CINHAL, Cochrane library (inception-January 2019) for randomised control trials or their follow-up studies reporting prediction, prognosis, intervention or management outcomes in twin pregnancy. The study characteristics, outcomes definitions and measurements were extracted and descriptively analysed. RESULTS: 49 RCTs and 8 follow-up studies evaluated 21 interventions, 1257 outcomes, categorised into 170 unique outcomes. 65 % of trials included all twin pregnancies, 12 % DCDA and 11 % MCDA only or MCMA and MCDA. Five (9 %) papers were prediction/ prognosis RCT's and 52 (91 %) related to an intervention. Of interventions, 40 (77 %) were medical, 34 (85 %) for preterm birth; 12 (23 %) surgical, 6 (50 %) related to TTTS interventions (83 % for monochrorionic studies). Commonest domains were: 'Neonatal' 77 %, 'Delivery' 70 % and 'Survival' 67 %. Least reported were longer term outcomes for 'Infant' or 'Parental'. CONCLUSIONS: Twin pregnancy outcomes are diverse and complex. This is related to the need to address maternal, single and double fetal outcomes and different types of chorionicity. The lack of outcome standardisation in selection, definition and reporting hinders evidence synthesis and the selection of outcomes important to women and health care professionals thus limiting the effectiveness of research.

Aspirin for preventing adverse outcomes in low risk nulliparous women with singleton pregnancies: A systematic review and meta-analysis.

OBJECTIVE: To assess the effects of aspirin in pregnancy for the prevention of adverse outcomes in low risk, nulliparous women with singleton pregnancies. STUDY DESIGN: Medline, Embase, CINAHL, the Cochrane library, Web of Science and clinicaltrials.gov were searched from inception until February 2020. Randomised controlled trials were eligible for inclusion where women were nulliparous, had singleton pregnancies and no other risk factors for pre-eclampsia such as diabetes or pre-existing hypertension. Primary outcomes were pre-eclampsia, gestational hypertension and eclampsia. Secondary outcomes included; pre-term birth, postpartum haemorrhage, antepartum haemorrhage, miscarriage, small for gestational age (SGA), fetal growth restriction (FGR), birthweight and further markers of maternal and neonatal morbidity and mortality. The results were combined into meta-analysis where appropriate. RESULTS: Ten studies were eligible for inclusion involving 23,162 women. Two studies (involving 214 women) used aspirin doses of 100 mg, with the remainder using smaller doses. There was no significant difference found in the risk of developing pre-eclampsia between women receiving aspirin compared to no aspirin (relative risk [RR] 0.70, 95 % confidence interval [CI] 0.47-1.05, p = 0.08). Women receiving aspirin had a reduced risk of having a preterm birth <34 weeks (RR 0.50, 95 % CI 0.26-0.96, p = 0.04), and reduced risk of having a SGA neonate (RR 0.94, 95 % CI 0.89-1.00, p = 0.04). An increase in birthweight was seen when aspirin was received (mean difference 105.17 g, 95 % CI 12.38 g-197.96 g, p = 0.03) and there was no increase in risk of postpartum or antepartum haemorrhage in those receiving aspirin (RR 1.24, 95 % CI 0.90-1.71, p = 0.19 and RR 1.06, 95 % CI 0.66-1.70, p = 0.81 respectively). CONCLUSION: The results did not demonstrate a significant difference amongst low risk nulliparous women in the risks of pre-eclampsia or gestational hypertensive disorders with aspirin administration. Although we found significantly improved fetal growth parameters and prevention of preterm birth in women receiving aspirin, there were few eligible studies, with those included generally providing low quality evidence and many studies using aspirin doses ≤100 mg, commenced late in pregnancy. More research in the form of a high quality randomised controlled trial is needed before recommendations can be made.

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 2020.

Vaginal preparation with chlorhexidine at cesarean section to reduce endometritis and prevent sepsis: A randomized pilot trial (PREPS).

INTRODUCTION: Cesarean sections are the most common major operation worldwide. One in 10 women develops a surgical-site infection after cesarean section. The PREPS pilot trial was developed to assess the feasibility of a randomized controlled trial of vaginal cleansing with chlorhexidine before cesarean section, to reduce infectious morbidity. MATERIAL AND METHODS: A multi-center, open-label, parallel-group pilot randomized controlled trial across 4 UK maternity units. Women aged ≥16 years, undergoing elective or emergency cesarean section, ≥34 weeks of gestation, and able to give informed consent were eligible. Women were randomized 1:1 to chlorhexidine 0.05% or no cleansing and were followed up until 6 weeks after cesarean section. The feasibility of a larger randomized controlled trial was assessed by the pilot trial's recruitment, ability to use verbal consent in an emergency, adherence, follow-up and withdrawal rates. The main clinical outcome collected was Center for Disease Control and Prevention (CDC) classification of endometritis at 30 days. Trial registration number is ISRCTN33435996. RESULTS: A total of 320 women (128% of target) were randomized. Of these, 93% (95% CI 89%-95%) received their allocated intervention. Of the 88 women who had an emergency cesarean section, verbal consent was initially given by 32 (36%) women, with the remainder having sufficient time to give written consent. Endometritis (CDC definition) was collected from medical notes of 96% of women, 68% (95% CI 63%-73%) were followed up at both 14 and 30 days by telephone, and we were able to collect patient-reported outcomes. In the vaginal cleansing arm 2/152 (1.3%) women had endometritis compared with 1/155 (0.7%) in the no cleansing arm (RR 2.08, 95% CI 0.19-22.31). CONCLUSIONS: It is possible to perform a randomized controlled trial in women undergoing an elective or emergency cesarean section, using a verbal-followed-by-written consent process, while maintaining high adherence and retaining women in the trial.

Are prophylactic adjunctive macrolides efficacious against caesarean section surgical site infection: A systematic review and meta-analysis.

Surgical site infection (SSI) post- caesarean section (CS) remains high, prophylactic adjunctive macrolides may reduce this. This systematic review and meta-analysis evaluated whether adjunctive prophylactic macrolides administered at CS reduce the risk of endometritis and wound infection. MEDLINE, EMBASE, CINHAL and the Cochrane library were searched from inception to July-2018. Observational and randomised studies investigating women undergoing a CS receiving standard prophylactic antibiotics, adjunctive prophylactic macrolides and assessed any SSI outcome was included. Data was double-extracted. Studies were included in a meta-analysis if the same study design and SSI outcome was used. Risk ratios were calculated and heterogeneity was assessed using the I2 test. Five studies were included in the systematic review and four in the meta-analysis. Two RCT's (n = 2610) found that macrolides significantly reduce the risk of wound infection RR [0.34; 95 %, 0.22 0.53] P = 0.00001 and endometritis RR [0.66; 95 %, 0.52, 0.85] P = 0.001 with no evidence of heterogeneity (I2 = 0 %). Two cohort studies (n = 13,809) found that azithromycin significantly reduces the risk of endometritis RR [0.16; 95 %, 0.04-0.62] P = 0.008, however significant heterogeneity was seen. Macrolides significantly reduce the risk of endometritis and wound infection post-CS. An effectiveness evaluation of post-cord clamping administration is needed to eliminate fetal antibiotic exposure and the long term infant implications this may have.

The incidence of wound infection and dehiscence following childbirth-related perineal trauma: A systematic review of the evidence.

OBJECTIVES: Approximately 85% of vaginal births are affected by childbirth related perineal trauma, either spontaneously or as a result of an episiotomy. Perineal infection in the postnatal period is associated with wound dehiscence, granulation tissue formation, dyspareunia and pelvic floor dysfunction. Despite leading to long-term physical and psychological problems, the incidence of infection continues to remain unclear. This review is designed to determine the incidence of childbirth related perineal wound infection and dehiscence. STUDY DESIGN: A systematic review to determine the incidence of wound infection and dehiscence associated with childbirth-related perineal trauma. Medline, Embase and Cinahl databases were searched from inception to September 2018 using MeSH, textwords and appropriate word variants to ensure capturing all relevant studies. No restrictions were placed on birth mode, degree of trauma, parity, country or language. RESULTS: 23 studies were included (11 cohort, 2 case control and 10 reporting incidence). Reported incidence of childbirth-related perineal trauma wound infection ranged from 0.1%-23.6% and wound dehiscence from 0.21%-24.6%. Quality assessment of included studies exposed inadequacies in several methodological areas. There was great clinical heterogeneity amongst the studies, particularly regarding perineal wound infection definition and confirmation, making effective synthesis of the data almost impossible. CONCLUSION: Despite the known high occurrence of perineal trauma during childbirth and associated long-term morbidities, this review clearly demonstrates the true incidence of infection remains largely unknown. This can be attributed to multiple factors including lack of high level evidence around understanding 'normal' perineal wound healing, absence of a core outcome set for childbirth-related perineal trauma and that women present to a variety of healthcare settings for treatment. It is vital that a validated childbirth-related perineal trauma diagnostic tool and core outcome set are developed for use in future studies to facilitate improved diagnosis and treatment and reduce long term morbidities of women affected by childbirth-related perineal trauma wound infection and dehiscence.

Quantitative fibronectin to help decision-making in women with symptoms of preterm labour (QUIDS) part 1: Individual participant data meta-analysis and health economic analysis.

INTRODUCTION: The aim of the QUIDS study is to develop a decision support tool for the management of women with symptoms and signs of preterm labour, based on a validated prognostic model using quantitative fetal fibronectin (qfFN) concentration, in combination with clinical risk factors. METHODS AND ANALYSIS: The study will evaluate the Rapid fFN 10Q System (Hologic, Marlborough, Massachusetts) which quantifies fFN in a vaginal swab. In part 1 of the study, we will develop and internally validate a prognostic model using an individual participant data (IPD) meta-analysis of existing studies containing women with symptoms of preterm labour alongside fFN measurements and pregnancy outcome. An economic analysis will be undertaken to assess potential cost-effectiveness of the qfFN prognostic model. The primary endpoint will be the ability of the prognostic model to rule out spontaneous preterm birth within 7 days. Six eligible studies were identified by systematic review of the literature and five agreed to provide their IPD (n=5 studies, 1783 women and 139 events of preterm delivery within 7 days of testing). ETHICS AND DISSEMINATION: The study is funded by the National Institute of Healthcare Research Health Technology Assessment (HTA 14/32/01). It has been approved by the West of Scotland Research Ethics Committee (16/WS/0068). PROSPERO REGISTRATION NUMBER: CRD42015027590. VERSION: Protocol version 2, date 1 November 2016.

Study protocol: quantitative fibronectin to help decision-making in women with symptoms of preterm labour (QUIDS) part 2, UK Prospective Cohort Study.

INTRODUCTION: The aim of the QUIDS study is to develop a decision support tool for the management of women with symptoms and signs of preterm labour, based on a validated prognostic model using quantitative fetal fibronectin (fFN) concentration, in combination with clinical risk factors. METHODS AND ANALYSIS: The study will evaluate the Rapid fFN 10Q System (Hologic, Marlborough, Massachusetts, USA) which quantifies fFN in a vaginal swab. In QUIDS part 2, we will perform a prospective cohort study in at least eight UK consultant-led maternity units, in women with symptoms of preterm labour at 22+0 to 34+6 weeks gestation to externally validate a prognostic model developed in QUIDS part 1. The effects of quantitative fFN on anxiety will be assessed, and acceptability of the test and prognostic model will be evaluated in a subgroup of women and clinicians (n=30). The sample size is 1600 women (with estimated 96-192 events of preterm delivery within 7 days of testing). Clinicians will be informed of the qualitative fFN result (positive/negative) but be blinded to quantitative fFN result. Research midwives will collect outcome data from the maternal and neonatal clinical records. The final validated prognostic model will be presented as a mobile or web-based application. ETHICS AND DISSEMINATION: The study is funded by the National Institute of Healthcare Research Health Technology Assessment (HTA 14/32/01). It has been approved by the West of Scotland Research Ethics Committee (16/WS/0068). VERSION: Protocol V.2, Date 1 November 2016. TRIAL REGISTRATION NUMBER: ISRCTN 41598423andCPMS: 31277.

The first antenatal diagnosis of KBG syndrome: a microdeletion at chromosome 16q24.2q24.3 containing multiple genes including ANKRD11 associated with the disorder.

The loss of ANKRD11 gene confirms the diagnosis of KBG syndrome but does not elucidate the pediatric phenotype providing a counseling challenge. With the expansion of prenatal diagnosis, and the potential to perform whole-exome sequencing antenatally, we must describe the genetic abnormalities, antenatal ultrasound findings, and phenotype concurrently to facilitate counseling.