Predictive RNA profiles for early and very early spontaneous preterm birth.

BACKGROUND: Spontaneous preterm birth remains the main driver of childhood morbidity and mortality. Because of an incomplete understanding of the molecular pathways that result in spontaneous preterm birth, accurate predictive markers and target therapeutics remain elusive. OBJECTIVE: This study sought to determine if a cell-free RNA profile could reveal a molecular signature in maternal blood months before the onset of spontaneous preterm birth. STUDY DESIGN: Maternal samples (n=242) were obtained from a prospective cohort of individuals with a singleton pregnancy across 4 clinical sites at 12-24 weeks (nested case-control; n=46 spontaneous preterm birth <35 weeks and n=194 term controls). Plasma was processed via a next-generation sequencing pipeline for cell-free RNA using the Mirvie RNA platform. Transcripts that were differentially expressed in next-generation sequencing cases and controls were identified. Enriched pathways were identified in the Reactome database using overrepresentation analysis. RESULTS: Twenty five transcripts associated with an increased risk of spontaneous preterm birth were identified. A logistic regression model was developed using these transcripts to predict spontaneous preterm birth with an area under the curve =0.80 (95% confidence interval, 0.72-0.87) (sensitivity=0.76, specificity=0.72). The gene discovery and model were validated through leave-one-out cross-validation. A unique set of 39 genes was identified from cases of very early spontaneous preterm birth (<25 weeks, n=14 cases with time to delivery of 2.5±1.8 weeks); a logistic regression classifier on the basis of these genes yielded an area under the curve=0.76 (95% confidence interval, 0.63-0.87) in leave-one-out cross validation. Pathway analysis for the transcripts associated with spontaneous preterm birth revealed enrichment of genes related to collagen or the extracellular matrix in those who ultimately had a spontaneous preterm birth at <35 weeks. Enrichment for genes in insulin-like growth factor transport and amino acid metabolism pathways were associated with spontaneous preterm birth at <25 weeks. CONCLUSION: Second trimester cell-free RNA profiles in maternal blood provide a noninvasive window to future occurrence of spontaneous preterm birth. The systemic finding of changes in collagen and extracellular matrix pathways may serve to identify individuals at risk for premature cervical remodeling, with growth factor and metabolic pathways implicated more often in very early spontaneous preterm birth. The use of cell-free RNA profiles has the potential to accurately identify those at risk for spontaneous preterm birth by revealing the underlying pathophysiology, creating an opportunity for more targeted therapeutics and effective interventions.

Cervicovaginal microbiota and metabolome predict preterm birth risk in an ethnically diverse cohort.

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.

Cervicovaginal natural antimicrobial expression in pregnancy and association with spontaneous preterm birth.

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.

Shock index thresholds to predict adverse outcomes in maternal hemorrhage and sepsis: A prospective cohort study.

INTRODUCTION: Shock index (SI) is a predictor of hemodynamic compromise in obstetric patients. The SI threshold for action is not well understood. We aimed to evaluate SI thresholds as predictors of outcomes in obstetric patients. MATERIAL AND METHODS: We undertook a prospective cohort study at three South African hospitals of women with postpartum hemorrhage (n = 283) or maternal sepsis (n = 126). The "first" and "worst" SI following diagnosis were recorded. SI was compared with conventional vital signs as predictors of outcomes. The performance of SI <.9, SI .9-1.69 and SI ≥1.7 to predict outcomes (maternal death; Critical Care Unit admission; major procedure; hysterectomy) and hemorrhage-specific outcomes (lowest hemoglobin <70 g/l; blood transfusion ≥4 IU) were evaluated. RESULTS: "First" SI was one of two best performing vital signs for every outcome in postpartum hemorrhage and sepsis. In hemorrhage, risk of all outcomes increased with increasing "first" SI; for blood transfusion ≥4 IU odds ratio was 4.24 (95% confidence interval 1.25-14.36) for SI ≥1.7 vs SI .9-1.69. In sepsis, risk of all outcomes increased with increasing "worst" SI. Sensitivity, specificity, positive and negative predictive values of "first" SI <.9 vs SI ≥.9 for maternal death were 100.0%, 55.2%, 4.6% and 100.0%, respectively, in hemorrhage and 80.0%, 50.4%, 12.3% and 96.7%, respectively, in sepsis. CONCLUSIONS: The shock index was a consistent predictor of outcomes compared with conventional vital signs in postpartum hemorrhage and sepsis. SI <.9 performed well as a rule-out test and SI .9-1.69 and SI ≥1.7 indicated increased risk of all outcomes in both cohorts. These thresholds may alert to the need for urgent intervention and prevent maternal deaths.

Development and evaluation of a novel Vital Signs Alert device for use in pregnancy in low-resource settings.

OBJECTIVES: Haemorrhage, hypertension, sepsis and abortion complications (often from haemorrhage or sepsis) contribute to 60% of all maternal deaths. Each is associated with vital signs (blood pressure (BP) and pulse) abnormalities, and the majority of deaths are preventable through simple and timely intervention. This paper presents the development and evaluation of the CRADLE Vital Signs Alert (VSA), an accurate, low-cost and easy-to-use device measuring BP and pulse with an integrated traffic light early warning system. The VSA was designed to be used by all cadres of healthcare providers for pregnant women in low-resource settings with the aim to prevent avoidable maternal mortality and morbidity. METHODS: The development and the mixed-methods clinical evaluation of the VSA are described. RESULTS: Preliminary fieldwork identified that introduction of BP devices to rural clinics improved antenatal surveillance of BP in pregnant women. The aesthetics of the integrated traffic light system were developed through iterative qualitative evaluation. The traffic lights trigger according to evidence-based vital sign thresholds in hypertension and haemodynamic compromise from haemorrhage and sepsis. The VSA can be reliably used as an auscultatory device, as well as its primary semiautomated function, and is suitable as a self-monitor used by pregnant women. CONCLUSION: The VSA is an accurate device incorporating an evidence-based traffic light early warning system. It is designed to ensure suitability for healthcare providers with limited training and may improve care for women in pregnancy, childbirth and in the postnatal period.

Maternal and perinatal adverse outcomes in women with pre-eclampsia cared for at facility-level in South Africa: a prospective cohort study.

BACKGROUND: Hypertensive disorders of pregnancy contribute to 14% of all maternal deaths, the majority of which occur in low- and middle-income countries. The aim of the study was to describe the maternal and perinatal clinical outcomes of women with pre-eclampsia living in middle- and low-income countries. METHODS: The study was a prospective observational study of women with pre-eclampsia (n = 1547, 42 twin pregnancies) at three South African tertiary facilities. Using stepwise logistic regression model area under the receiver operating characteristic curve (AUROC) values, the association between maternal baseline and admission characteristics and risk of adverse outcomes was evaluated. Main outcome measures were eclampsia, kidney injury and perinatal death. RESULTS: In 1547 women with pre-eclampsia, 16 (1%) died, 147 (9.5%) had eclampsia, four (0.3%) had a stroke and 272 (17.6%) had kidney injury. Of the 1589 births, there were 332 (21.0%) perinatal deaths; of these, 281 (84.5%) were stillbirths. Of 1308 live births, 913 (70.0%) delivered <37 completed weeks and 544 (41.7%) delivered <34 weeks' gestation. Young maternal age (AUROC = 0.76, 95% confidence interval (CI) = 0.71-0.80) and low Body Mass Index BMI (AUROC 0.65, 95% CI = 0.59-0.69) were significant predictors of eclampsia. Highest systolic blood pressure had the strongest association with kidney injury, (AUROC = 0.64, 95% CI = 0.60-0.68). Early gestation at admission was most strongly associated with perinatal death (AUROC = 0.81, 95% CI = 0.77-0.84). CONCLUSIONS: The incidence of pre-eclampsia complications, perinatal death and preterm delivery in women referred to tertiary care in South Africa was much higher than reported in other low- and middle-income studies and despite access to tertiary care interventions. Teenage mothers and those with low BMI were at highest risk of eclampsia. This information could be used to inform guidelines, the research agenda and policy.

Is recreational running associated with earlier delivery and lower birth weight in women who continue to run during pregnancy? An international retrospective cohort study of running habits of 1293 female runners during pregnancy.

BACKGROUND: Increasingly, women of reproductive age participate in recreational running, but its impact on pregnancy outcome is unknown. We investigated whether running affects gestational age at delivery and birth weight as indicators of cervical integrity and placental function, respectively. METHODS: 1293 female participants were recruited from parkrun, which organises weekly runs involving 1.25 million runners across 450 parks worldwide. Those under 16 or unable to provide outcome data were excluded. Women were categorised according to whether they continued to run during pregnancy or not. Those who continued were further stratified dependent on average weekly kilometres, and which trimester they ran until. Retrospectively collected primary outcomes were gestational age at delivery and birthweight centile. Other outcomes included assisted vaginal delivery rate and prematurity at clinically important gestations. RESULTS: There was no significant difference in gestational age at delivery: 279.0 vs 279.6 days (mean difference 0.6 days, CI -1.3 to 2.4 days; P=0.55) or birthweight centile: 46.9%vs 44.9% (mean difference 2.0%, CI -1.3% to -5.3%; P=0.22) in women who stopped running and those who continued, respectively. Assisted vaginal delivery rate was increased in women who ran: 195/714 (27%) vs 128/579 (22%) (OR 1.32; CI 1.02 to 1.71; P=0.03). CONCLUSION: Continuing to run during pregnancy does not appear to affect gestational age or birthweight centile, regardless of mean weekly distance or stage of pregnancy. Assisted vaginal delivery rates were higher in women who ran, possibly due to increased pelvic floor muscle tone. Randomised prospective analysis is necessary to further explore these findings.

Early warning system hypertension thresholds to predict adverse outcomes in pre-eclampsia: A prospective cohort study.

OBJECTIVES: To evaluate the association between blood pressure (BP) measurements and adverse outcomes in women with pre-eclampsia. STUDY DESIGN: A prospective cohort study of women with pre-eclampsia admitted to three South African tertiary facilities. BP was measured using the CRADLE Vital Signs Alert (VSA), incorporated with a traffic light early warning system; green: systolic BP <140 mmHg and diastolic BP <90 mmHg, yellow: systolic BP 140-159 and/or diastolic BP 90-109 mmHg (but neither is above the upper threshold), red: systolic BP ≥160 mmHg and/or diastolic BP ≥110 mmHg. MAIN OUTCOME MEASURES: Maternal: death, eclampsia, stroke, kidney injury; process measures: magnesium sulfate use, Critical Care Unit (CCU) admission; perinatal: stillbirth, neonatal death, preterm delivery. RESULTS: Of 1547 women with pre-eclampsia (including 42 twin pregnancies), 33.0% of women triggered a red light on admission and 78.6% at their highest BP. Severe hypertension and adverse outcomes were common across yellow and red categories. Comparing admission red to yellow lights, there was a significant increase in kidney injury (OR 1.74, CI 1.31-2.33, trend test p = .003), magnesium sulfate use (OR 3.40, CI 2.24-5.18, p < .001) and CCU admission (OR 1.50, CI 1.18-1.91, p < .001), but not for maternal death, eclampsia, extended perinatal death or preterm delivery. CONCLUSION: The CRADLE VSA, with integrated traffic light early warning system, can identify women who are hypertensive, at increased risk of severe pre-eclampsia complications and in need of escalation of care. Women who triggered a red light were at increased risk of kidney injury, magnesium sulfate use and CCU admission.

Host Defense Peptide Expression in Human Cervical Cells and Regulation by 1,25-Dihydroxyvitamin D3 in the Presence of Cytokines and Bacterial Endotoxin.

Host defense peptides (HDPs) in the pregnant female reproductive tract provide protection against infection. The relationship between HDPs and infection/inflammation is poorly understood. Therefore, we investigated the regulation of HDPs by 1α, 25-dihydroxyvitamin D3 (1,25-(OH)2) in the presence/absence of infectious/inflammatory agents. Endocervical epithelial cells (END1/E6E7, n = 6) were exposed to 1,25-(OH)2, calcipotriol, interleukin 1ß (IL-1ß), granulate-macrophage colony-stimulating factor (GM-GSF), and lipopolysaccharide (LPS). Elafin, human beta defensin (hBD2), cathelicidin, secretory leucocyte protease inhibitor, interleukin 8, 1,25-(OH)2 receptor, and toll-like receptor 4 (TLR4) expression was determined using quantitative polymerase chain reaction and/or enzyme-linked immunosorbent assay. Host defense peptide gene and protein expression was assessed in cervicovaginal cells/fluid, respectively, from first trimester pregnant women (n = 8-12). Interleukin 1ß induced elafin and hBD2. The 1,25-(OH)2 induced cathelicidin expression in the presence of IL-1ß and LPS. The 1,25-(OH)2 also attenuated IL-1ß-induced IL-8 expression and LPS enhancement of TLR4. Host defense peptides and TLR4 profiles in cervicovaginal cells and fluid samples from pregnant women were similar to END1/E6E7 cells. In conclusion, HDPs are differentially regulated in END1/E6E7 cells. The 1,25-(OH)2 induction of cathelicidin and suppression of IL-8 highlights a mechanism by which 1,25-(OH)2 supplementation could enhance the pregnant innate immune defenses.

Prediction of spontaneous preterm birth using fetal fibronectin in women with a low-lying placenta.

OBJECTIVE: To determine the effect of a low-lying placenta on the concentration of quantitative fetal fibronectin (qfFN) in the cervicovaginal fluid (CVF), and predictive accuracy for spontaneous preterm birth in asymptomatic high-risk women (18 + 0-24 + 0 weeks gestation). METHODS: Median concentrations of qfFN were compared in women who had a low-lying placenta, covering the cervical os (n = 61) to matched controls (n= 61) without a low-lying placenta. Proportions of women with raised qfFN concentrations (>10 ng/ml), and false positive and negative rates (FPR and FNR) for spontaneous preterm delivery were also compared. RESULTS: The median concentration of qfFN in women with low-lying placenta was 5.0 ng/mL, compared with 6.0 ng/mL in controls. Proportion of women with raised levels (>10 ng/mL), positive levels (>50 ng/mL) and very high levels (>200 ng/mL) were similar in both groups (62.3% versus 59.0%, 16.3% versus 22.0% and 6.5% versus 4.9%, p > 0.05 for all thresholds). The FPR and FNR rate for delivery before 34 and 37 weeks were also comparable (FPR 90.0% versus 85.7% and 80.0% versus 78.6%; FNR 5.8% versus 4.3% and 9.8% versus 8.5%). CONCLUSIONS: CVF qfFN concentrations in asymptomatic high-risk women are not affected by the presence of a low-lying placenta.

The effect of blood staining on cervicovaginal quantitative fetal fibronectin concentration and prediction of spontaneous preterm birth.

OBJECTIVE: Spontaneous preterm birth is the leading cause of neonatal morbidity and mortality. Cervicovaginal fetal fibronectin (fFN) has enhanced prediction of preterm birth and, more recently, quantified results have become available so that management can planned more effectively and targeted to individual women. Manufacture guidelines stipulate that fetal fibronectin (fFN) samples should be discarded in the presence of moderate to heavy vaginal bleeding but there hasn't yet been any formal investigation into the effect of blood staining on fetal fibronectin concentration and subsequent preterm birth prediction. The objective for this study was to determine the impact of blood stained swabs on quantitative fetal fibronectin (qfFN) concentration and prediction of spontaneous preterm birth (sPTB) in asymptomatic high-risk women. STUDY DESIGN: Predefined blinded sub-analysis of a larger prospective study of qfFN in asymptomatic women at high-risk of preterm labour. Women with and without blood stained swabs were matched for gestational age at testing and delivery, risk factors and cervical length measurement. RESULTS: Median fFN concentration in blood stained swabs (n=58) was 66ng/ml vs. 7.5ng/ml in the controls (n=58) (p<0.0001). At ≥50ng/ml threshold the false positive ratio (FPR) in blood stained was 25/33 (75.8%) vs. 8/15 (53%) in controls, (risk difference 22.4; -6.8 to 51.6, p=0.18). At ≥50ng/ml threshold the false-negative ratio (FNR) in blood stained was 2/25 (8.0%) vs. 1/43 (2.3%) in controls (risk difference -5.7; -17.2 to 5.9, p=0.55). At each threshold 10, 50 and 200ng/ml blood stained swabs had higher sensitivity but lower specificity for predicting preterm birth. Receiver Operating Characteristic (ROC) curve, the strongest global measure of test performance, for prediction of delivery at <34 weeks gestation was similar in blood stained vs. control groups. (0.78 vs. 0.84) in blood stained vs. control groups respectively. CONCLUSION: Blood stained swabs have elevated qfFN concentrations but may still have predictive value, and clinical utility. Very low fFN values (<10ng/ml) are especially reassuring and indicate lower risk of delivery than non-blood stained swabs. The higher false positive rate must be noted and explained to the patient.

Determination of Normal Ranges of Shock Index and Other Haemodynamic Variables in the Immediate Postpartum Period: A Cohort Study.

OBJECTIVE: To determine the normal ranges of vital signs, including blood pressure (BP), mean arterial pressure (MAP), heart rate (HR) and shock index (SI) (HR/systolic BP), in the immediate postpartum period to inform the development of robust obstetric early warning scores. STUDY DESIGN: We conducted a secondary analysis of a prospective observational cohort study evaluating vital signs collected within one hour following delivery in women with estimated blood loss (EBL) <500ml (316 women) delivering at a UK tertiary centre over a one-year period. Simple and multiple linear regression were used to explore associations of demographic and obstetric factors with SI. RESULTS: Median (90% reference range) was 120 (100-145) for systolic BP, 75 (58-90) for diastolic BP, 90 (73-108) for MAP, 81 (61-102) for HR, and 0.66 (0.52-0.89) for SI. Third stage Syntometrine® administration was associated with a 0.03 decrease in SI (p = 0.035) and epidural use with a 0.05 increase (p = 0.003). No other demographic or obstetric factors were associated with a change in shock index in this cohort. CONCLUSION: This is the first study to determine normal ranges of maternal BP, MAP, HR and SI within one hour of birth, a time of considerable haemodynamic adjustment, with minimal effect of demographic and obstetric factors demonstrated. The lower 90% reference point for systolic BP and upper 90% reference point for HR correspond to triggers used to recognise shock in obstetric practice, as do the upper 90% reference points for systolic and diastolic BP for obstetric hypertensive triggers. The SI upper limit of 0.89 in well postpartum women supports current literature suggesting a threshold of 0.9 as indicating increased risk of adverse outcomes.

Rationale and design of SuPPoRT: a multi-centre randomised controlled trial to compare three treatments: cervical cerclage, cervical pessary and vaginal progesterone, for the prevention of preterm birth in women who develop a short cervix.

BACKGROUND: Clinically, once a woman has been identified as being at risk of spontaneous preterm birth (sPTB) due to a short cervical length, a decision regarding prophylactic treatment must be made. Three interventions have the potential to improve outcomes: cervical cerclage (stitch), vaginal progesterone and cervical pessary. Each has been shown to have similar benefit in reduction of sPTB, but there have been no randomised control trials (RCTs) to compare them. METHODS: This open label multi-centre UK RCT trial, will evaluate whether the three interventions are equally efficacious to prevent premature birth in women who develop a short cervix (<25 mm on transvaginal ultrasound). Participants will be asymptomatic and between 14+0 and 23+6 weeks' gestation in singleton pregnancies. Eligible women will be randomised to cervical cerclage, Arabin pessary or vaginal progesterone (200 mg once daily) (n = 170 women per group). The obstetric endpoints are premature birth rate <37 weeks' of gestation (primary), 34 weeks and 30 weeks (secondary outcomes) and short-term neonatal outcomes (a composite of death and major morbidity). It will also explore whether intervention success can be predicted by pre-intervention biomarker status. DISCUSSION: Preterm birth is the leading cause of perinatal morbidity and mortality and a short cervix is a useful way of identifying those most at risk. However, best management of these women has presented a clinical conundrum for decades. Given the promise offered by cerclage, Arabin pessary and vaginal progesterone for prevention of preterm birth in individual trials, direct comparison of these prophylactic interventions is now essential to establish whether one treatment is superior. If, as we hypothesise, the three interventions are equally efficacious, this study will empower women to make a choice of treatments based on personal preference and quality of life issues also explored by the study. Our exploratory analysis into whether the response to intervention is related to the pre-intervention biomarker status further our understanding of the pathophysiology of spontaneous preterm birth and help focus future research questions. TRIAL REGISTRATION: EudraCT Number: 2015-000456-15 . Registered 11th March 2015.

Quantitative fetal fibronectin and cervical length to predict preterm birth in asymptomatic women with previous cervical surgery.

BACKGROUND: Quantitative fetal fibronectin testing has demonstrated accuracy for prediction of spontaneous preterm birth in asymptomatic women with a history of preterm birth. Predictive accuracy in women with previous cervical surgery (a potentially different risk mechanism) is not known. OBJECTIVE: We sought to compare the predictive accuracy of cervicovaginal fluid quantitative fetal fibronectin and cervical length testing in asymptomatic women with previous cervical surgery to that in women with 1 previous preterm birth. STUDY DESIGN: We conducted a prospective blinded secondary analysis of a larger observational study of cervicovaginal fluid quantitative fetal fibronectin concentration in asymptomatic women measured with a Hologic 10Q system (Hologic, Marlborough, MA). Prediction of spontaneous preterm birth (<30, <34, and <37 weeks) with cervicovaginal fluid quantitative fetal fibronectin concentration in primiparous women who had undergone at least 1 invasive cervical procedure (n = 473) was compared with prediction in women who had previous spontaneous preterm birth, preterm prelabor rupture of membranes, or late miscarriage (n = 821). Relationship with cervical length was explored. RESULTS: The rate of spontaneous preterm birth <34 weeks in the cervical surgery group was 3% compared with 9% in previous spontaneous preterm birth group. Receiver operating characteristic curves comparing quantitative fetal fibronectin for prediction at all 3 gestational end points were comparable between the cervical surgery and previous spontaneous preterm birth groups (34 weeks: area under the curve, 0.78 [95% confidence interval 0.64-0.93] vs 0.71 [95% confidence interval 0.64-0.78]; P = .39). Prediction of spontaneous preterm birth using cervical length compared with quantitative fetal fibronectin for prediction of preterm birth <34 weeks of gestation offered similar prediction (area under the curve, 0.88 [95% confidence interval 0.79-0.96] vs 0.77 [95% confidence interval 0.62-0.92], P = .12 in the cervical surgery group; and 0.77 [95% confidence interval 0.70-0.84] vs 0.74 [95% confidence interval 0.67-0.81], P = .32 in the previous spontaneous preterm birth group). CONCLUSION: Prediction of spontaneous preterm birth using cervicovaginal fluid quantitative fetal fibronectin in asymptomatic women with cervical surgery is valid, and has comparative accuracy to that in women with a history of spontaneous preterm birth.

Quantitative fetal fibronectin predicts preterm birth in women with bulging fetal membranes.

OBJECTIVE: To assess the predictive value of quantitative fetal fibronectin (fFN) concentration in cervicovaginal fluid for spontaneous preterm birth in women with bulging fetal membranes. STUDY DESIGN: This was a prospective observational study from five UK tertiary centres of a cohort of women with singleton pregnancy and bulging fetal membranes presenting between 18 and 32 weeks of gestation (n=62), in the period 2010-2014. fFN concentrations in cervicovaginal fluid were measured both quantitatively and qualitatively at presentation in all women. Predictive statistics and receiver operating characteristic (ROC) curves were calculated for both tests to predict spontaneous preterm birth within 14 days from testing and before 34 weeks of gestation. RESULTS: 62 eligible women with bulging fetal membranes were recruited from screening of 2571 women at high risk of preterm birth. The median gestational age was 24(+0) (LQ-UQ, 21(+2)-25(+3)) at presentation and 34(+4) (25(+2)-39(+0)) at delivery, with a median time from testing to delivery of 58 days (17-110). Concentration of quantitative fFN at presentation correlated negatively with time to delivery (Spearman's rs=-0.615, p<0.001). The area under the ROC curve for quantitative fFN testing was 0.81 (95% CI 0.69-0.94) for prediction of spontaneous preterm birth within 14 days, and 0.84 (0.73-0.95) before 34 weeks of gestation. CONCLUSION: Quantitative fFN has a role in predicting spontaneous preterm birth even in women with bulging fetal membranes, suggesting that fFN leakage could potentially be an active process. This may aid the clinical management of this high-risk group in the future.

Quantitative Fetal Fibronectin at 18 Weeks of Gestation to Predict Preterm Birth in Asymptomatic High-Risk Women.

OBJECTIVE: To compare quantitative fetal fibronectin measurement from 18 to 21 weeks of gestation to measurement at 22-27 weeks of gestation for the prediction of spontaneous preterm birth. METHODS: In a prospective cohort study, we studied the accuracy of cervicovaginal fluid quantitative fetal fibronectin concentrations measured between 18 0/7 weeks of gestation and 21 6/7 weeks of gestation in high-risk asymptomatic women to predict spontaneous preterm birth before 34 weeks of gestation. Predefined fibronectin thresholds were 10 or greater, 50 or greater, and 200 ng/mL or greater. Diagnostic accuracy of the early test (n=898) was compared with the standard test performed between 22 0/7 and 27 6/7 weeks of gestation (n=691) in the same cohort. Subgroup analysis was performed according to cervical length measurement. RESULTS: Of 898 women, 8.7% delivered spontaneously before 34 weeks of gestation. Only 3.8% of the women with concentrations less than 10 ng/mL (65% of test results) delivered before 34 weeks of gestation. A concentration threshold of 10 ng/mL measured at 18 and 22 weeks of gestation had comparably high sensitivity (early 0.71, 95% confidence interval 0.60-0.81; standard 0.76, 0.63-0.87) and negative predictive value (early 0.96, 0.94-0.98; standard 0.97, 0.95-0.99) for delivery before 34 weeks of gestation. Specificity was also comparable (early 0.69, 0.65-0.72; standard 0.70, 0.66-0.74). A threshold of 200 ng/mL had high specificity (early 0.96, 0.94-0.98; standard 0.96, 0.94-0.97) with lower sensitivity (early 0.26, 0.17-0.37; standard 0.35, 0.22-0.49). Consideration of cervical length strengthened prediction. CONCLUSION: Quantitative cervicovaginal fetal fibronectin measured from 18 to 21 weeks of gestation has similar predictive value as measurement at 22-27 weeks of gestation for prediction of spontaneous preterm birth. Low fibronectin concentrations are associated with spontaneous preterm birthrates approaching population background levels.

Vital Sign Prediction of Adverse Maternal Outcomes in Women with Hypovolemic Shock: The Role of Shock Index.

OBJECTIVE: To determine the optimal vital sign predictor of adverse maternal outcomes in women with hypovolemic shock secondary to obstetric hemorrhage and to develop thresholds for referral/intensive monitoring and need for urgent intervention to inform a vital sign alert device for low-resource settings. STUDY DESIGN: We conducted secondary analyses of a dataset of pregnant/postpartum women with hypovolemic shock in low-resource settings (n = 958). Using receiver-operating curve analysis, we evaluated the predictive ability of pulse, systolic blood pressure, diastolic blood pressure, shock index, mean arterial pressure, and pulse pressure for three adverse maternal outcomes: (1) death, (2) severe maternal outcome (death or severe end organ dysfunction morbidity); and (3) a combined severe maternal and critical interventions outcome comprising death, severe end organ dysfunction morbidity, intensive care admission, blood transfusion ≥ 5 units, or emergency hysterectomy. Two threshold parameters with optimal rule-in and rule-out characteristics were selected based on sensitivities, specificities, and positive and negative predictive values. RESULTS: Shock index was consistently among the top two predictors across adverse maternal outcomes. Its discriminatory ability was significantly better than pulse and pulse pressure for maternal death (p<0.05 and p<0.01, respectively), diastolic blood pressure and pulse pressure for severe maternal outcome (p<0.01), and systolic and diastolic blood pressure, mean arterial pressure and pulse pressure for severe maternal outcome and critical interventions (p<0.01). A shock index threshold of ≥ 0.9 maintained high sensitivity (100.0) with clinical practicality, ≥ 1.4 balanced specificity (range 70.0-74.8) with negative predictive value (range 93.2-99.2), and ≥ 1.7 further improved specificity (range 80.7-90.8) without compromising negative predictive value (range 88.8-98.5). CONCLUSIONS: For women with hypovolemic shock from obstetric hemorrhage, shock index was consistently a strong predictor of all adverse outcomes. In lower-level facilities in low resource settings, we recommend a shock index threshold of ≥ 0.9 indicating need for referral, ≥ 1.4 indicating urgent need for intervention in tertiary facilities and ≥ 1.7 indicating high chance of adverse outcome. The vital sign alert device incorporated values 0.9 and 1.7; however, all thresholds will be prospectively validated and clinical pathways for action appropriate to setting established prior to clinical implementation.

Quantitative fetal fibronectin to predict spontaneous preterm birth: a review.

Spontaneous preterm birth (sPTB) is the leading cause of neonatal morbidity and mortality globally. Accurate prediction of sPTB would enable targeting of interventions such as admission to hospital, antenatal corticosteroids, magnesium sulphate and in utero transfer as well as guiding prophylactic treatment (e.g., cerclage or progesterone). Measurement of fetal fibronectin concentration in the cervicovaginal fluid is a known predictor of sPTB. Traditionally a positive/negative test (defined by a threshold of 50 ng/ml), recent work has demonstrated improved prediction when used as a quantitative test, whereby the concentration of fetal fibronectin is measured by an automated bedside reader. This review examines the evidence surrounding the use of quantitative fetal fibronectin in asymptomatic women at high risk of sPTB, as well as those with symptoms of threatened sPTB.