Longitudinal change in cervical length following vaginal or abdominal cervical cerclage: a randomized comparison

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

A translational approach to studying preterm labour

Preterm labour continues to be a major contributor to neonatal and infant morbidity. Recent data from the USA indicate that the number of preterm deliveries (including those associated with preterm labour) has risen in the last 20 years by 30%. This increase is despite considerable efforts to introduce new therapies for the prevention and treatment of preterm labour and highlights the need to assess research in this area from a fresh perspective. In this paper we discuss i) the limitations of our knowledge concerning prediction, prevention and treatment of preterm labour and ii) future multidisciplinary strategies for improving our approach

Midwifery continuity of care versus standard maternity care for women at increased risk of preterm birth : a hybrid implementation–effectiveness, randomised controlled pilot trial in the UK

Background Midwifery continuity of care is the only health system intervention shown to reduce preterm birth (PTB) and improve perinatal survival, but no trial evidence exists for women with identified risk factors for PTB. We aimed to assess feasibility, fidelity, and clinical outcomes of a model of midwifery continuity of care linked with a specialist obstetric clinic for women considered at increased risk for PTB. Methods and findings We conducted a hybrid implementation–effectiveness, randomised, controlled, unblinded, parallel-group pilot trial at an inner-city maternity service in London (UK), in which pregnant women identified at increased risk of PTB were randomly assigned (1:1) to either midwifery continuity of antenatal, intrapartum, and postnatal care (Pilot study Of midwifery Practice in Preterm birth Including women’s Experiences [POPPIE] group) or standard care group (maternity care by different midwives working in designated clinical areas). Pregnant women attending for antenatal care at less than 24 weeks’ gestation were eligible if they fulfilled one or more of the following criteria: previous cervical surgery, cerclage, premature rupture of membranes, PTB, or late miscarriage; previous short cervix or short cervix this pregnancy; or uterine abnormality and/or current smoker of tobacco. Feasibility outcomes included eligibility, recruitment and attrition rates, and fidelity of the model. The primary outcome was a composite of appropriate and timely interventions for the prevention and/or management of preterm labour and birth. We analysed by intention to treat. Between 9 May 2017 and 30 September 2018, 334 women were recruited; 169 women were allocated to the POPPIE group and 165 to the standard group. Mean maternal age was 31 years; 32% of the women were from Black, Asian, and ethnic minority groups; 70% were in employment; and 46% had a university degree. Nearly 70% of women lived in areas of social deprivation. More than a quarter of women had at least one pre-existing medical condition and multiple risk factors for PTB. More than 75% of antenatal and postnatal visits were provided by a named/partner midwife, and a midwife from the POPPIE team was present at 80% of births. The incidence of the primary composite outcome showed no statistically significant difference between groups (POPPIE group 83.3% versus standard group 84.7%; risk ratio 0.98 [95% confidence interval (CI) 0.90 to 1.08]; p = 0.742). Infants in the POPPIE group were significantly more likely to have skin-to-skin contact after birth, to have it for a longer time, and to breastfeed immediately after birth and at hospital discharge. There were no differences in other secondary outcomes. The number of serious adverse events was similar in both groups and unrelated to the intervention (POPPIE group 6 versus standard group 5). Limitations of this study included the limited power and the nonmasking of group allocation; however, study assignment was masked to the statistician and researchers who analysed the data. Conclusions In this study, we found that it is feasible to set up and achieve fidelity of a model of midwifery continuity of care linked with specialist obstetric care for women at increased risk of PTB in an inner-city maternity service in London (UK), but there is no impact on most outcomes for this population group. Larger appropriately powered trials are needed, including in other settings, to evaluate the impact of relational continuity and hypothesised mechanisms of effect based on increased trust and engagement, improved care coordination, and earlier referral on disadvantaged communities, including women with complex social factors and social vulnerability. Trial registration We prospectively registered the pilot trial on the UK Clinical Research Network Portfolio Database (ID number: 31951, 24 April 2017). We registered the trial on the International Standard Randomised Controlled Trial Number (ISRCTN) (Number: 37733900, 21 August 2017) and before trial recruitment was completed (30 September 2018) when informed that prospective registration for a pilot trial was also required in a primary clinical trial registry recognised by WHO and the International Committee of Medical Journal Editors (ICMJE). The protocol as registered and published has remained unchanged, and the analysis conforms to the original plan

Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses

Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth. We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134. We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163 947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73-2·89]; I2=59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74-0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35-0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02-0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 μmol/L versus four (0·28%; 0·08-0·72) of 1412 cases with total bile acids of 40-99 μmol/L (hazard ratio [HR] 2·35 [95% CI 0·52-10·50]; p=0·26), and versus 18 (3·44%; 2·05-5·37) of 524 cases for bile acids of 100 μmol/L or more (HR 30·50 [8·83-105·30]; p<0·0001). The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 μmol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery. Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust

Limited Relationship between Cervico-Vaginal Fluid Cytokine Profiles and Cervical Shortening in Women at High Risk of Spontaneous Preterm Birth

Objective: to determine the relationship between high vaginal pro-inflammatory cytokines and cervical shortening in women at high risk of spontaneous preterm labor and to assess the influence of cervical cerclage and vaginal progesterone on this relationship. Methods: this prospective longitudinal observational study assessed 112 women with at least one previous preterm delivery between 16 and 34 weeks’ gestation. Transvaginal cervical length was measured and cervico-vaginal fluid sampled every two weeks until 28 weeks. If the cervix shortened (<25 mm) before 24 weeks’ gestation, women (cases) were randomly assigned to cerclage or progesterone and sampled weekly. Cytokine concentrations were measured in a subset of cervico-vaginal fluid samples (n = 477 from 78 women) by 11-plex fluid-phase immunoassay. Results: all 11 inflammatory cytokines investigated were detected in cervico-vaginal fluid from women at high risk of preterm birth, irrespective of later cervical shortening. At less than 24 weeks’ gestation and prior to intervention, women destined to develop a short cervix (n = 36) exhibited higher cervico-vaginal concentrations than controls (n = 42) of granulocyte-macrophage colony-stimulating factor [(GM-CSF) 16.2 fold increase, confidence interval (CI) 1.8–147; p = 0.01] and monocyte chemotactic protein-1 [(MCP-1) 4.8, CI 1.0–23.0; p = 0.05]. Other cytokines were similar between cases and controls. Progesterone treatment did not suppress cytokine concentrations. Interleukin (IL)-6, IL-8, granulocyte colony-stimulating factor (G-CSF), interferon (IFN)-γ and tumour necrosis factor (TNF)-α concentrations were higher following randomization to cerclage versus progesterone (p<0.05). Cerclage, but not progesterone treatment, was followed by a significant increase in cervical length [mean 11.4 mm, CI 5.0–17.7; p<0.001]. Conclusions: although GM-CSF and MCP-1 cervico-vaginal fluid concentrations were raised, the majority of cervico-vaginal cytokines did not increase in association with cervical shortening. Progesterone treatment showed no significant anti-inflammation action on cytokine concentrations. Cerclage insertion was associated with an increase in the majority of inflammatory markers and cervical length

Midwifery continuity of care versus standard maternity care for women at increased risk of preterm birth : a hybrid implementation–effectiveness, randomised controlled pilot trial in the UK

Background: Midwifery continuity of care is the only health system intervention shown to reduce preterm birth (PTB) and improve perinatal survival, but no trial evidence exists for women with identified risk factors for PTB. We aimed to assess feasibility, fidelity, and clinical outcomes of a model of midwifery continuity of care linked with a specialist obstetric clinic for women considered at increased risk for PTB. Methods and findings: We conducted a hybrid implementation–effectiveness, randomised, controlled, unblinded, parallel-group pilot trial at an inner-city maternity service in London (UK), in which pregnant women identified at increased risk of PTB were randomly assigned (1:1) to either midwifery continuity of antenatal, intrapartum, and postnatal care (Pilot study Of midwifery Practice in Preterm birth Including women’s Experiences [POPPIE] group) or standard care group (maternity care by different midwives working in designated clinical areas). Pregnant women attending for antenatal care at less than 24 weeks' gestation were eligible if they fulfilled one or more of the following criteria: previous cervical surgery, cerclage, premature rupture of membranes, PTB, or late miscarriage; previous short cervix or short cervix this pregnancy; or uterine abnormality and/or current smoker of tobacco. Feasibility outcomes included eligibility, recruitment and attrition rates, and fidelity of the model. The primary outcome was a composite of appropriate and timely interventions for the prevention and/or management of preterm labour and birth. We analysed by intention to treat. Between 9 May 2017 and 30 September 2018, 334 women were recruited; 169 women were allocated to the POPPIE group and 165 to the standard group. Mean maternal age was 31 years; 32% of the women were from Black, Asian, and ethnic minority groups; 70% were in employment; and 46% had a university degree. Nearly 70% of women lived in areas of social deprivation. More than a quarter of women had at least one pre-existing medical condition and multiple risk factors for PTB. More than 75% of antenatal and postnatal visits were provided by a named/partner midwife, and a midwife from the POPPIE team was present at 80% of births. The incidence of the primary composite outcome showed no statistically significant difference between groups (POPPIE group 83.3% versus standard group 84.7%; risk ratio 0.98 [95% confidence interval (CI) 0.90 to 1.08]; p = 0.742). Infants in the POPPIE group were significantly more likely to have skin-to-skin contact after birth, to have it for a longer time, and to breastfeed immediately after birth and at hospital discharge. There were no differences in other secondary outcomes. The number of serious adverse events was similar in both groups and unrelated to the intervention (POPPIE group 6 versus standard group 5). Limitations of this study included the limited power and the nonmasking of group allocation; however, study assignment was masked to the statistician and researchers who analysed the data. Conclusions: In this study, we found that it is feasible to set up and achieve fidelity of a model of midwifery continuity of care linked with specialist obstetric care for women at increased risk of PTB in an inner-city maternity service in London (UK), but there is no impact on most outcomes for this population group. Larger appropriately powered trials are needed, including in other settings, to evaluate the impact of relational continuity and hypothesised mechanisms of effect based on increased trust and engagement, improved care coordination, and earlier referral on disadvantaged communities, including women with complex social factors and social vulnerability. Trial registration: We prospectively registered the pilot trial on the UK Clinical Research Network Portfolio Database (ID number: 31951, 24 April 2017). We registered the trial on the International Standard Randomised Controlled Trial Number (ISRCTN) (Number: 37733900, 21 August 2017) and before trial recruitment was completed (30 September 2018) when informed that prospective registration for a pilot trial was also required in a primary clinical trial registry recognised by WHO and the International Committee of Medical Journal Editors (ICMJE). The protocol as registered and published has remained unchanged, and the analysis conforms to the original plan