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 R 2 of 0.34. The economic analysis found that the prognostic model was cost-effective compared with using qualitative fetal fibronectin at a threshold for hospital admission and treatment of ≥ 2% risk of preterm birth within 7 days. Limitations The outcome proportion (spontaneous preterm birth within 7 days of test) was 2.9% in the validation study. This is in line with other studies, but having slightly fewer than 100 events is a limitation in model validation. Conclusions A prognostic model that included quantitative fetal fibronectin and clinical risk factors showed excellent performance in the prediction of spontaneous preterm birth within 7 days of test, was cost-effective and can be used to inform a decision support tool to help guide management decisions for women with threatened preterm labour. Future work The prognostic model will be embedded in electronic maternity records and a mobile telephone application, enabling ongoing data collection for further refinement and validation of the model. Study registration This study is registered as PROSPERO CRD42015027590 and Current Controlled Trials ISRCTN41598423. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 52. See the NIHR Journals Library website for further project information.

A Combination of Cervicovaginal Fluid Glutamate, Acetate and D-Lactate Identified Asymptomatic Low-Risk Women Destined to Deliver Preterm: a Prospective Cohort Study

Due to the modest predictive capacities and limited clinical application of transvaginal ultrasonographic cervical length (CL) and quantitative fetal fibronectin (qfFN) in pregnant women at low risk of preterm birth (PTB), we sought to determine the utility of cervicovaginal fluid (CVF) metabolites (by-products of host-microbial metabolism) for prediction of spontaneous PTB in asymptomatic low-risk women at mid-gestation. This was a prospective sub-cohort study from the ECCLIPPx study cohort. CVF from asymptomatic singleton women (20–22 weeks, n = 168) without a prior history of PTB were analysed for metabolites by enzyme-based spectrophotometry. CL, vaginal pH and qfFN were also measured. Correlation and predictive analyses were performed by Spearman’s correlation, and binary logistic regression and area under receiver operating characteristic curve (AUC), respectively. Of the 168 women enrolled, only CVF samples from 135 (80.4%) women were analysed. There were 6/135 (4.4%) spontaneous PTB (sPTBs), with two of these pregnancies ending ≤ 28 weeks’ gestation. Individually (AUC, 95% CI), only glutamate (0.72, 0.64–0.80) and CL (0.69, 0.60–0.77) were predictive of PTB. However, five multivariable models that more accurately predicted sPTB were also identified, i.e. a combination of: glutamate, acetate and D-lactate (GAD, 0.82, 0.74–0.89); CL and qfFN only (0.78, 0.70–0.85); CL, qfFN, glutamate and acetate (0.88, 0.81–0.93); CL, qfFN and GAD (0.94, 0.88–0.98); and GAD and pH (0.86, 0.79–0.92). Correlations between CL, pH and qfFN and metabolites were also observed. In this cohort, a midtrimester combination of CVF glutamate, acetate and D-lactate predicted preterm birth more accurately than individual metabolites, cervical length and fetal fibronectin with a very low false-positive rate and high positive predictive value. Further testing in populations with higher preterm birth rates is required.

Serum Liberation of Fetal Fibronectin Variants in Patients with Pulmonary Hypertension: ED-A+ Fn as Promising Novel Biomarker of Pulmonary Vascular and Right Ventricular Myocardial Remodeling

Background and Aims: Pulmonary Hypertension (PH) represents an aetiologically and clinically heterogeneous disorder accompanied by a severely impaired prognosis. Key steps of PH pathogenesis are vascular and right ventricular myocardial remodelling entailing the re-occurrence of fetal variants of the cell adhesion modulating protein fibronectin (Fn) being virtually absent in healthy adult tissues. These variants are liberated into circulation and are therefore qualified as excellent novel serum biomarkers. Moreover, these molecules might serve as promising therapeutic targets. The current study was aimed at quantifying the serum levels of two functionally important fetal Fn variants (ED-A+ and ED-B+ Fn) in patients suffering from PH due to different aetiologies compared to healthy controls. Methods: Serum levels of ED-A+ and ED-B+ Fn were quantified using novel ELISA protocols established and validated in our group in 80 PH patients and 40 controls. Results were analysed with respect to clinical, laboratory, echocardiographic and functional parameters. Results: Serum levels of ED-A+ Fn (p = 0.001) but not ED-B+ Fn (p = 0.722) were significantly increased in PH patients compared to healthy controls. Thus, the following analyses were performed only for ED-A+ Fn. When dividing PH patients into different aetiological groups according to current ESC guidelines, the increase in ED-A+ Fn in PH patients compared to controls remained significant for group 1 (p = 0.032), 2 (p = 0.007) and 3 (p = 0.001) but not for group 4 (p = 0.156). Correlation analysis revealed a significant relation between ED-A+ Fn and brain natriuretic peptide (BNP) (r = 0.310; p = 0.002), six minutes’ walk test (r = −0.275; p = 0.02) and systolic pulmonary artery pressure (PAPsys) (r = 0.364; p < 0.001). By logistic regression analysis (backward elimination WALD) including a variety of potentially relevant patients’ characteristics, only chronic kidney disease (CKD) (OR: 8.866; CI: 1.779–44.187; p = 0.008), C reactive protein (CRP) (OR: 1.194; CI: 1.011–1.410; p = 0.037) and ED-A+ Fn (OR: 1.045; CI: 1.011–1.080; p = 0.009) could be identified as independent predictors of the presence of PH. Conclusions: Against the background of our results, ED-A+ Fn could serve as a promising novel biomarker of PH with potential value for initial diagnosis and aetiological differentiation. Moreover, it might contribute to more precise risk stratification of PH patients. Beyond that, the future role of ED-A+ Fn as a therapeutic target has to be evaluated in further studies.

The contemporary value of dedicated preterm birth clinics for high-risk singleton pregnancies: fifteen-year outcomes from a leading maternal centre

Objectives Preterm birth clinics provide dedicated obstetric care to women at high risk of spontaneous preterm birth (SPTB). There remains a lack of conclusive evidence to support the overall utility of such clinics, attributable to a paucity and heterogeneity of primary data. This study audits Australia’s largest and oldest dedicated preterm birth clinic with the aim to add primary data to the area and offer opportunities for similar clinics to align practice. Methods A retrospective audit of referrals to the Preterm Labour Clinic at the Royal Women’s Hospital, Melbourne, Australia, between 2004 and 2018 was conducted. 1,405 singleton pregnancies met inclusion criteria. The clinic’s key outcomes, demographics, predictive tests and interventions were analysed. The primary outcomes were SPTB before 37, 34 and 30 weeks’ gestation. Results The overall incidence of SPTB in the clinic was 21.2% (n=294). Linear regression showed reductions in the adjusted rates of overall SPTB and pre-viable SPTB (delivery <24 weeks) from 2014 (108%; 8%) to 2018 (65%; 2% respectively). Neonatal morbidity and post-delivery intensive care admission concurrently declined (p=0.02; 0.006 respectively). Rates of short cervix (cervical length <25 mm) increased over time (2018: 30.9%) with greater uptake of vaginal progesterone for treatment. Fetal fibronectin, mid-trimester short cervix, and serum alkaline phosphatase were associated with SPTB on logistic regression. Conclusions Dedicated preterm birth clinics can reduce rates of SPTB, particularly deliveries before 24 weeks’ gestation, and improve short-term neonatal outcomes in pregnant women at risk of preterm birth.

Preterm Labour

Preterm delivery is defined as delivery before 37 weeks completed gestation. It represents a major cause of neonatal morbidity and mortality and accounts for 5–10% of all deliveries. Cervical length assessment between 16–24 weeks and positive fetal fibronectin beyond 21 weeks gestation are proved to useful tools in prediction of preterm labour. Treating asymptomatic bacteruia and bacterial vaginosis in high-risk women reduces the incidence of preterm labour. Cervical cerclage is recommended to reduce the incidence of preterm birth in women with 2nd trimester losses and those with cervical length of 25 mm or less on transvaginal ultrasound between 16–24 weks gestation. Atosiban and nifidipine are currently the agents of choice in tocolysis. Antenal steriods in womens with threating preterm labour reduces the perinatal morbidties. Magnisum sulphate role is established for neuroprotection especially in extreme gestations between 24–30 weeks. Vaginal delivery is mode of choice for delivery with consideration to avoid fetal blood sampling, fetal scalp electrodes and ventouse prior to 34 weeks gestations. Caesarean section is considered for obstetric reasons that guide labour management at term.

Preterm labor: issues of prognosis, prevention and management (Literature rewiew)

Preterm labor is the leading cause of neonatal mortality and the most common cause for antenatal hospitalization. Approximately 15 million babies are born preterm each year worldwide. Of those, one million babies die before the age of 5, which is 18% of all deaths of children at this age. 35% of early and late neonatal mortality (under 28 days of age) is associated with preterm birth.The pathophysiology of preterm labor includes at least four major pathogenetic mechanisms. The studied components of this process are premature activation of the maternal or fetal hypothalamic-pituitary-adrenal system, inflammation or infection, decidual hemorrhage and pathological overdistension of the uterus. The diagnosis of preterm labor is based on the determination of concomitant regular uterine contractions and cervical changes. Vaginal bleeding and/or rupture of the amniotic membranes only increase the likelihood of this diagnosis. To improve the accuracy of diagnosis and assess the potential risk of preterm birth in the presence of symptoms in pregnant women, it is proposed to use such diagnostic tests as transvaginal ultrasound to measure cervical length; detection in vaginal fluids of fetal fibronectin (fFN), phosphorylated protein-1, which binds insulin-like growth factor (IGFBP-1), placental alpha-microglobulin, the ratio of insulin-like growth factorebinding protein 4 (IBP4) and sex hormoneebinding globulin (SHBG) – PreTRM-test.Correct identification of women in the true preterm labor allows performing appropriate actions, which results in better outcomes for the newborn. These are using of corticosteroids to prevent respiratory distress syndrome (RDS) of the newborn; prevention of group B streptococcal infection; magnesium sulfate to protect the baby’s nervous system; transportation to the institution of the third level of perinatal care, which can provide a newborn with appropriate medical care. Preventative and therapeutic measures for women, which have a high risk of preterm labor, include taking progesterone, cervical cerclage and an application of obstetric pessary.

Reproductive health interventions for Inuit youth in the north: a scoping review

Background Inuit have thrived in the northern regions of Canada and Alaska for thousands of years. Recent evidence suggests that Inuit in this region have experienced systemic barriers to reproductive health with resulting disparities in reproductive health-related outcomes including those among youth. Northern youth-focused reproductive health intervention research or evaluations have not to date been well summarized. The objective of this scoping review was to summarize the literature over the past twenty years focusing on reproductive health interventions for adolescents in northern Inuit communities. Methods English-language articles from 2000 to 2020 were identified from seven scientific databases, a general internet search and a review of relevant websites. Two reviewers screened titles, abstracts and full texts and included articles if they mentioned a reproductive health intervention and pertained, directly or indirectly, to reproductive health for Inuit aged 10–19 in northern communities. Results Seventeen articles met the inclusion criteria, across six themes: (1) Barriers to reproductive health interventions in the north; (2) Northern midwifery; (3) Northern birthing centres; (4) Fetal fibronectin tests for identifying high-risk pregnancies; (5) Prenatal education classes; and (6) Interventions to improve access to and quality of reproductive health supports. Conclusion Overall there is relatively limited evidence base specific to reproductive health interventions and northern Inuit youth. What does exist largely focuses on maternal health interventions and is inclusive of but not specific to youth. There is some evidence that youth specific educational programs, participatory action research approaches and the promotion of northern birthing centres and midwifery can improve reproductive health for adolescents and young mothers in northern Inuit communities. Future initiatives should focus on the creation and evaluation of culturally relevant and youth specific interventions and increasing community and youth participation in intervention research for better reproductive health.

Fetal Fibronectin in Cervical and Vaginal Secretions as a Predictor of Preterm Delivery

This article reviews the study “Fetal Fibronectin in Cervical and Vaginal Secretions as a Predictor of Preterm Delivery,” published in The New England Journal of Medicine in 1991 by Lockwood et al. The study examined the use of fetal fibronectin found in cervicovaginal secretions as a marker for preterm delivery in symptomatic women presenting with preterm contractions or with preterm premature rupture of membranes. The chapter reviews the findings of this study as well as the place of fetal fibronectin testing in current obstetrical practice based on subsequent studies.