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Background: The CRADLE Vital Signs Alert intervention (an accurate easy-to-use device that measures blood pressure and pulse with inbuilt traffic-light early warning system, and focused training package) was associated with reduced rates of eclampsia and maternal death when trialled in urban areas in Sierra Leone. Subsequently, implementation was successfully piloted as evidenced by measures of fidelity, feasibility and adoption. The CRADLE-5 trial will examine whether national scale-up, including in the most rural areas, will reduce a composite outcome of maternal and fetal mortality and maternal morbidity and will evaluate how the CRADLE package can be embedded sustainably into routine clinical pathways., Methods: CRADLE-5 is a stepped-wedge cluster-randomised controlled trial of the CRADLE intervention compared to routine maternity care across eight rural districts in Sierra Leone (Bonthe, Falaba, Karene, Kailahun, Koinadugu, Kono, Moyamba, Tonkolili). Each district will cross from control to intervention at six-weekly intervals over the course of 1 year (May 2022 to June 2023). All women identified as pregnant or within six-weeks postpartum presenting for maternity care in the district are included. Primary outcome data (composite rate of maternal death, stillbirth, eclampsia and emergency hysterectomy) will be collected. A mixed-methods process and scale-up evaluation (informed by Medical Research Council guidance for complex interventions and the World Health Organization ExpandNet tools) will explore implementation outcomes of fidelity, adoption, adaptation and scale-up outcomes of reach, maintenance, sustainability and integration. Mechanisms of change and contextual factors (barriers and facilitators) will be assessed. A concurrent cost-effectiveness analysis will be undertaken., Discussion: International guidance recommends that all pregnant and postpartum women have regular blood pressure assessment, and healthcare staff are adequately trained to respond to abnormalities. Clinical effectiveness to improve maternal and perinatal health in more rural areas, and ease of integration and sustainability of the CRADLE intervention at scale has yet to be investigated. This trial will explore whether national scale-up of the CRADLE intervention reduces maternal and fetal mortality and severe maternal adverse outcomes and understand the strategies for adoption, integration and sustainability in low-resource settings. If successful, the aim is to develop an adaptable, evidence-based scale-up roadmap to improve maternal and infant outcomes., Trial Registration: ISRCTN 94429427. Registered on 20 April 2022., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Cervical cerclage has been shown to reduce the risk of recurrent spontaneous preterm birth in a high-risk patient population; however, the mechanism is not well understood. Transabdominal cerclage is superior to low and high vaginal cerclage in reducing early spontaneous preterm birth and fetal loss in women with previous failed vaginal cerclage. Cervical length measurements are commonly used to monitor high-risk women and may explain the mechanism of success., Objective: This study aimed to evaluate the rate of change in longitudinal cervical length after randomized placement of low transvaginal, high transvaginal, or transabdominal cerclage in women with a previous failed vaginal cerclage., Study Design: This was a planned analysis of longitudinal transvaginal ultrasound cervical length measurements from patients enrolled in the Vaginal Randomised Intervention of Cerclage trial, a randomized controlled trial comparing transabdominal cerclage or high transvaginal cerclage with low transvaginal cerclage. Cervical length measurements at specific gestational ages were compared over time and between groups, using generalized estimating equations fitted using the maximum-likelihood random-effects estimator. In addition, cervical length measurements were compared in women with transabdominal cerclage placed before and during pregnancy. The diagnostic accuracy of cervical length as a predictor of spontaneous preterm birth at <32 weeks of gestation was explored., Results: This study included 78 women who underwent longitudinal cervical length assessment (70% of the analyzed cohort) with a history of failed cerclage, of whom 25 (32%) were randomized to low transvaginal cerclage, 26 (33%) to high transvaginal cerclage, and 27 (35%) to transabdominal cerclage. Abdominal cerclage was superior to low (P=.008) and high (P=.001) vaginal cerclage at maintaining cervical length over the surveillance period (14 to 26 weeks of gestation) (+0.08 mm/week, 95% confidence interval, -0.40 to 0.22; P=.580). On average, the cervical length was 1.8 mm longer by the end of the 12-week surveillance period in women with transabdominal cerclage (+1.8 mm; 95% confidence interval, -7.89 to 4.30; P=.564). High vaginal cerclage was no better than low cervical cerclage in the prevention of cervical shortening; the cervix shortened by 13.2 mm over 12 weeks in those with low vaginal cerclage (95% confidence interval, -21.7 to -4.7; P=.002) and by 20 mm over 12 weeks in those with high vaginal cerclage (95% confidence interval, -33.1 to -7.4; P=.002). Preconception transabdominal cerclage resulted in a longer cervix than those performed during pregnancy; this difference was significant after 22 weeks of gestation (48.5 mm vs 39.6 mm; P=.039). Overall, cervical length was an excellent predictor of spontaneous preterm birth at <32 weeks of gestation (receiver operating characteristic curve, 0.92; 95% confidence interval, 0.82-1.00)., Conclusion: In women with a previous failed cervical cerclage, in the next pregnancy, the cervical length in women treated with vaginal cerclage funneled and shortened over time, whereas there was preservation of cervical length in women who receive transabdominal cerclage. Cervical length remained longer in transabdominal procedures performed before pregnancy than in transabdominal procedures performed during pregnancy. Overall, cervical length was an excellent predictor of spontaneous preterm birth in our cohort. Our findings may explain the mechanism of benefit for transabdominal cerclage, with its high placement better maintaining the structural integrity of the cervix at the level of the internal os., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the performance of the predictive markers of spontaneous preterm birth, cervicovaginal quantitative fetal fibronectin (fFN) and cervical length, in asymptomatic high-risk women with transabdominal, history-indicated or ultrasound-indicated cervical cerclage., Methods: This was a secondary analysis of a prospective cohort of asymptomatic high-risk women with cervical cerclage and no other prophylactic intervention (including progesterone), who attended the preterm birth clinic at a central London teaching hospital between October 2010 and September 2016. Women had either transabdominal cerclage, placed prior to conception, history-indicated cerclage, placed before 14 weeks' gestation, or ultrasound-indicated cerclage for a short cervix (< 25 mm), placed before 24 weeks. All women underwent serial cervical length assessment on transvaginal ultrasound in the second trimester (16-28 weeks), and quantitative fFN testing from 18 weeks onward. Test performance was analyzed for the prediction of spontaneous preterm birth before 30 weeks (cerclage failure), 34 weeks and 37 weeks, using receiver-operating-characteristics (ROC)-curve analysis., Results: Overall, 181 women were included in the analysis. Cervical length and fFN were strong predictors of spontaneous preterm birth before 30 weeks in women with cerclage, with areas under the ROC curve (AUC) of 0.86 (95% CI, 0.79-0.94) and 0.84 (95% CI, 0.75-0.92), respectively. Cervical length was a better predictor of preterm birth before 30 weeks in women with history-indicated compared to those with ultrasound-indicated cerclage, although both showed clinical utility (AUC, 0.96 (95% CI, 0.91-1.00) vs 0.79 (95% CI, 0.66-0.91); P = 0.01). Quantitative fFN was a strong predictor of spontaneous preterm birth before 30 weeks in women with history-indicated cerclage (AUC, 0.91 (95% CI, 0.75-1.00)) and retained clinical utility in those with ultrasound-indicated cerclage (AUC, 0.76 (95% CI, 0.64-0.89)). There were no spontaneous deliveries before 34 weeks in women with a transabdominal cerclage, so AUC was not calculated. Delivery was delayed significantly in this group (P < 0.01)., Conclusions: Cervical length and quantitative fFN retain clinical utility for the prediction of spontaneous preterm birth in women with cervical cerclage, and prediction is best in women with a history-indicated stitch. These tests can be relied upon to discriminate risk and have utility when planning clinical management with regard to treatment failure. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Chorioamnionitis is present in up to 70% of spontaneous preterm births and is associated with poor maternal, fetal and neonatal outcomes., Objective: To explore the relationship between the neutrophil-to-lymphocyte ratio and histological chorioamnionitis in women who delivered preterm with no clinical signs or symptoms of infection., Study Design: This was a retrospective analysis of a cohort of women who delivered spontaneously between 16 and 36 +6 weeks at a tertiary UK hospital. Only women with placental histology and no signs of clinical infection were included. The neutrophil-to-lymphocyte ratio was calculated from a full blood count sample taken routinely within 24 h of delivery. The neutrophil-to-lymphocyte ratio was also calculated from first trimester booking bloods (<13 + 6 weeks) in a subgroup. Placental histopathology was categorised as either inflammatory (i.e. histologic chorioamnionitis, with or without evidence of fetal inflammatory response) or non-inflammatory (vascular pathology or a normal placenta)., Results: 169 women had available placental pathology and were included in the analysis. 70 % (118/169) had confirmed placental inflammation. The mean neutrophil-to-lymphocyte ratio was significantly raised in this group compared to those with normal (n = 24) or vascular (n = 27) pathology (inflammatory neutrophil-to-lymphocyte ratio 9.81 vs non-inflammatory neutrophil-to-lymphocyte ratio 6.53, p = 0.002. The delivery neutrophil-to-lymphocyte ratio had an area under the receiver operating characteristic curve of 0.69 (0.60 to 0.78) for predicting placental inflammation. A raised neutrophil-to-lymphocyte ratio (>6) was associated with an odds ratio of 5.2 (95 % CI 2.55 to 10.56) for histological chorioamnionitis, with a sensitivity of 80 % and negative predictive value of 86 %. A higher cut-off of 9 had a negative predictive value of 79 % for fetal inflammatory response., Conclusions: A raised neutrophil-to-lymphocyte ratio is associated with a 5-fold increased risk of histological chorioamnionitis in women who delivered early without signs or symptoms of infection. It was also raised at the time of preterm labour compared to the first trimester. A full blood count is an almost universal investigation in women admitted in preterm labour, often repeated, making this inexpensive and non-invasive ratio a useful additional antenatal biomarker in women admitted in spontaneous preterm labour at risk of subclinical chorioamnionitis and its associated poor outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: AS runs preterm birth studies commercially funded to institution. Further details of The BMJ policy on financial interests is here: https://www.bmj.com/sites/default/files/attachments/resources/2016/03/16-current-bmj-education-coi-form.pdf.

The syndrome of spontaneous preterm birth (sPTB) presents a challenge to mechanistic understanding, effective risk stratification, and clinical management. Individual associations between sPTB, self-reported ethnic ancestry, vaginal microbiota, metabolome, and innate immune response are known but not fully understood, and knowledge has yet to impact clinical practice. Here, we used multi-data type integration and composite statistical models to gain insight into sPTB risk by exploring the cervicovaginal environment of an ethnically heterogenous pregnant population (n = 346 women; n = 60 sPTB < 37 weeks' gestation, including n = 27 sPTB < 34 weeks). Analysis of cervicovaginal samples (10-15+6 weeks) identified potentially novel interactions between risk of sPTB and microbiota, metabolite, and maternal host defense molecules. Statistical modeling identified a composite of metabolites (leucine, tyrosine, aspartate, lactate, betaine, acetate, and Ca2+) associated with risk of sPTB < 37 weeks (AUC 0.752). A combination of glucose, aspartate, Ca2+, Lactobacillus crispatus, and L. acidophilus relative abundance identified risk of early sPTB < 34 weeks (AUC 0.758), improved by stratification by ethnicity (AUC 0.835). Increased relative abundance of L. acidophilus appeared protective against sPTB < 34 weeks. By using cervicovaginal fluid samples, we demonstrate the potential of multi-data type integration for developing composite models toward understanding the contribution of the vaginal environment to risk of sPTB.

There is much interest in the role of innate immune system proteins (antimicrobial peptides) in the inflammatory process associated with spontaneous preterm birth (sPTB). After promising pilot work, we aimed to validate the association between the antimicrobial peptides/proteins elafin and cathelicidin and sPTB. An observational cohort study of 405 women at high-risk, and 214 women at low-risk of sPTB. Protein concentrations of elafin and cathelicidin, and the enzyme human neutrophil elastase (HNE) were measured in over 1,000 cervicovaginal fluid (CVF) samples (10 to 24 weeks' gestation). Adjusted CVF cathelicidin and HNE concentrations (but not elafin) were raised in high-risk women who developed cervical shortening and who delivered prematurely and were predictive of sPTB < 37 weeks, with an area under the curve (AUC) of 0.75 (95% CI 0.68 to 0.81) for cathelicidin concentration at 14 to 15 +6  weeks. Elafin concentrations were affected by gestation, body mass index and smoking. CVF elafin in early pregnancy was modestly predictive of sPTB < 34 weeks (AUC 0.63, 0.56-0.70). Alterations in innate immune response proteins in early pregnancy are predictive of sPTB. Further investigation is warranted to understand the drivers for this, and their potential to contribute towards clinically useful prediction techniques.

Objective: Late miscarriage and preterm birth are frequently thought to be associated with inflammation and infection, although in most cases the underlying cause of early delivery remains unknown. The placenta is the organ that links mother and fetus during pregnancy, and postnatal examination may provide useful information about pathophysiology. The relationship between placental pathological lesions and predictive markers of early delivery has not been explored. We sought to characterize preterm deliveries according to placental pathology and relate these to the performance of reliable predictive markers, fetal fibronectin and cervical length., Study Design: This is a retrospective subanalysis from a larger prospective cohort study on sonographic cervical length, quantitative fetal fibronectin and risk of spontaneous preterm birth. Our cohort was comprised of high-risk asymptomatic women attending the Prematurity Surveillance Clinic at St Thomas' Hospital between 2002 and 2015, who went on to have a late miscarriage or preterm delivery (16-36 +6 weeks') and who had available placental histology. The placental pathology of these preterm deliveries was characterized according to the lesions identified, and categorized (according to the Redman classification) into inflammatory (e.g. chorioamnionitis) or non-inflammatory (histologically normal or vascular lesions indicating e.g. malperfusion). We sought to relate placental findings to the performance of reliable predictive markers, in women who delivered early. Standard clinical cut offs for cervical length (<25mm) and fetal fibronectin (>50ng/mL) were used to identify the proportion of preterm births that were accurately predicted by the tests or who showed a false negative result, in relation to their placental histology findings. Binomial logistic regression was carried out to evaluate the relationship between placental inflammation, quantitative fFN and cervical length as continuous variables., Results: 105 women who had a late miscarriage or preterm delivery (16-36 +6 weeks') and available placenta pathology were identified. 66% (42/64) of those with inflammatory placental pathology had a positive fetal fibronectin swab result compared to 15% (6/41) of those with non-inflammatory placental pathology (chi-squared 25.9, 95% CI 31.5 to 65.6, p<0.0001). A logistic regression model subanalysis of women in whom both CL and quantitative fFN results were available (n=66) revealed a highly statistically significant relationship with inflammatory placental lesions (p=0.003 and p=0.001 respectively). Placental inflammation was found to be associated with both increasing levels of fFN and a shortening cervix., Conclusion: There is a significant association between a positive fetal fibronectin result and underlying inflammatory pathology of the placenta, even more so than the recognized relationship with short cervical length. Infective morbidity may be increased in women and neonates with positive fetal fibronectin who deliver preterm., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To describe our initial outcome data following a shortened 6-week treatment protocol with percutaneous tibial nerve stimulation (PTNS) in women with overactive bladder syndrome (OABS) unresponsive to bladder retraining and anticholinergic therapy., Patients and Methods: This was a prospective observational study over a 6-month period. In all, 43 women with OABS refractory to medical therapy were treated with a shortened PTNS protocol that consisted of 6 weekly 30 min sessions. Bladder symptom diaries and health-related quality of life (HRQL) assessed using the short-form seven-item self-report. Incontinence Impact Questionnaire (IIQ-7) were completed before and after treatment. A positive response was defined as: (i) OAB symptoms no longer being bothersome; (ii) reduction by half in frequency episodes and (iii) reduction by 25% in IIQ-7 outcomes., Results: All 43 women (median age 55.3 years) completed six treatments with a positive response rate of 69.7%. In the positive responders, the median daytime and nocturnal frequency was reduced by half after 6 weeks of treatment (11.8 vs 6.9 and 3.5 vs 1.8, respectively, P < 0.05) and the patients reported fewer urge leak episodes per 24 h (median 3.5 vs 2.4, P < 0.05). The median IIQ-7 scores improved by 25% (30.4 vs 24.3, P < 0.05) in responders, while the median number of pads changed in 24 h also decreased by 34% (3.8 vs 2.5, P < 0.05). The median acceptability of the technique when scored by Visual Analogue Score was 9.6/10 and no side-effects were reported., Conclusion: A shortened 6-week treatment with PTNS appears to be successful, with a significant reduction in symptoms and improvement in HRQL. This early data suggest that the duration of treatment for peripheral neuromodulation can be halved compared with the conventional 12 weeks, which would make it more acceptable and cost effective for patients. A randomised controlled trial of 6 weeks vs 12 weeks of PTNS therapy would be useful in determining the optimal duration of treatment., (© 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.)

Overactive bladder syndrome is defined as a symptom syndrome which includes urinary urgency, with or without urge incontinence, usually accompanied by frequency (>8 micturitions/24 h) and nocturia. Conservative treatment usually comprises behavioural techniques, bladder retraining, pelvic floor re-education and pharmacotherapy but up to 30% of patients will remain refractory to treatment. Although second-line treatment options such as sacral nerve stimulation and intravesical botulinum A injections are valuable additions to the therapeutic arsenal, they are relatively invasive and can have serious side-effects. Inhibition of detrusor activity by peripheral neuromodulation of the posterior tibial nerve was first described in 1983, with recent authors further confirming a 60-80% positive response rate. This review was undertaken to examine published literature on percutaneous tibial nerve stimulation and to discuss outcome measures, maintenance therapy and prognostic factors of this technique.