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Background: Preterm birth (PTB) is a leading cause of neonatal mortality, such that the need for a rapid and accurate assessment for PTB risk is critical. Here, we developed a 3D printed microfluidic system that integrated solid-phase extraction (SPE) and microchip electrophoresis (μCE) of PTB biomarkers, enabling the combination of biomarker enrichment and labeling with μCE separation and fluorescence detection., Results: Reversed-phase SPE monoliths were photopolymerized in 3D printed devices. Microvalves in the device directed sample between the SPE monolith and the injection cross-channel in the serpentine μCE channel. Successful on-chip preconcentration, labeling and μCE separation of four PTB-related polypeptides were demonstrated in these integrated microfluidic devices. We further show the ability of these devices to handle complex sample matrices through the successful analysis of labeled PTB biomarkers spiked into maternal blood serum. The detection limit was 7 nM for the PTB biomarker, corticotropin releasing factor, in 3D printed SPE-μCE integrated devices., Significance: This work represents the first successful demonstration of integration of SPE and μCE separation of disease-linked biomarkers in 3D printed microfluidic devices. These studies open up promising possibilities for rapid bioanalysis of medically relevant analytes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GPN and ATW own shares in Acrea3D, a company that is commercializing 3D printers. The other authors have no conflicts to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Centrally collected Finnish national health register data on adverse pregnancy outcomes are available for research, but the validity of the data is largely unknown. Our aim was to compare the diagnoses of preeclampsia (PE), gestational diabetes (GDM), and preterm delivery from hospital records with the registry based diagnoses from the Finnish Care Register for Health Care (FCR). Data on gestational age at delivery from the Medical Birth Registry (MBR) was also studied., Methods: The Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) Study cohort was used as a data source. Each diagnosis was ascertained from electronic hospital records. The validity of diagnoses obtained by record linkage of FCR and MBR was assessed against the classification previously confirmed independently by a research nurse and a study physician., Results: Sensitivity of PE diagnoses in FCR was 80.3 % (95 % CI 78.3 % to 82.2 %) andspecificity 95.3 % (95 % CI 93.9 % to 96.4 %). Sensitivity for GDM was 64.1 % (95 % CI: 58.7 % - 69.3 %) and specificity 98.5 % (95 % CI: 97.9 % - 98.9 %), whereas sensitivity and specificity for preterm delivery were 32.4 % (95 % CI: 29.0 % - 36.0 %) and 99.7 % (95 % CI: 99.3 % - 99.9 %). Sensitivity of preterm delivery in the MBR was 99.1 % and specificity 99.9 %., Conclusions: FCR registry diagnoses for PE have satisfactory sensitivity and high specificity. Diagnoses for GDM and preterm delivery have lower sensitivity limiting their use in studies, and data from MBR should be preferred when studying preterm deliveries., 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 © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

We employed digital light processing-stereolithography 3D printing to create microfluidic devices with different designs for microchip electrophoresis (µCE). Short or long straight channel, and two- or four-turn serpentine channel microfluidic devices with separation channel lengths of 1.3, 3.1, 3.0, and 4.7 cm, respectively, all with a cross injector design, were fabricated. We measured current as a function of time and voltage to determine a separation time window and conditions for the onset of Joule heating in these designs. Separations in these devices were evaluated by performing µCE and measuring theoretical plate counts for electric field strengths near and above the onset of Joule heating, with fluorescently labeled glycine and phenylalanine as model analytes. We further demonstrated µCE of peptides and proteins related to preterm birth risk, showing increased peak capacity and resolution compared to previous results with 3D printed microdevices. These results mark an important step forward in the use of 3D printed microfluidic devices for rapid bioanalysis by µCE., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests GPN and ATW own shares in Acrea3D, a company that is commercializing 3D printers. The other authors have no conflicts to declare, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Spontaneous preterm birth (SPB) can't be predicted accurately nowadays. We aim to investigate the value of serum amyloid A(SAA) and interleukin-6(IL-6) for forecasting the risk of SPB., Methods: A total of 302 pregnant women who completed delivery in our hospital from January 2019 to December 2021 were included. According to gestational days, they were divided into the case group (28-33 +6 weeks, 41 cases; 34-36 +6 weeks, 96 cases) and the control group (37-42 weeks, 165 cases). The general data of the two groups were analyzed and the values of SAA and IL-6 in speculating the risk of SPB were studied in this study., Results: The levels of SAA and IL-6 in the case group were higher than those in the control group(P < 0.05), and the most practical value of SAA and IL-6 access SPB risk were 17.35 mg/L, 112.41 pg/mL respectively. The area under the ROC curve of diagnosis to predict SPB were 0.8849, 0.8664., Conclusions: The assessment of SPB risk by SAA and IL-6 bearscertain clinical value, which could assist clinicians in recognizing and evaluating the potential dangers of SPB., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Preterm birth is the largest single cause of infant death in the United States. A cervical length of <2.5 cm, measured in the mid-trimester, has been shown to identify individuals at increased risk. Uterine electromyography is an emerging technology for noninvasively assessing uterine bioelectrical activity. With its ability to characterize nuanced differences in myometrial signals, uterine electromyography assessments during the mid-trimester may provide insight into the mechanisms of cervical shortening., Objective: This study aimed to characterize uterine bioelectrical activity in pregnant individuals with short cervices in the mid-trimester compared with that of pregnant individuals of the same gestational age with normal cervical lengths., Study Design: This is a prospective cohort study of subjects with singleton, nonanomalous pregnancies between 16 weeks and 0 days and 22 weeks and 6 days of gestational age. Subjects with normal cervical length (≥3.0 cm) were compared with subjects with short cervical length (<2.5 cm). The short-cervical-length cohort was further stratified by history of preterm birth. Multichannel uterine electromyography recordings were obtained for ∼60 minutes using proprietary, directional electromyography sensors on the abdomen. Uterine electromyography signals were observed and classified in groups as spikes, short bursts, and bursts. Primary outcomes were relative expression of spike, short-burst, and burst uterine electromyography signals. Subgroup analyses assessed each signal percentage by cervical length, history of preterm birth, and gestational age at delivery. Differences in percentage of uterine electromyography signals according to cervical length were analyzed using nonparametric tests of significance., Results: Of the 28 included subjects, 10 had normal and 18 had short cervical length. There were 9 subjects with short cervical length and a history of preterm birth. Spikes were the most commonly recorded signals and were higher in the normal-cervical-length cohort (96.3% [interquartile range, 93.1%-100.0%]) than the short-cervical-length cohort (75.2% [interquartile range, 66.7%-92.0%], P=.001). In contrast, median percentages of short-bursts and bursts were significantly higher in subjects with a short cervical length (17.3% [interquartile range, 13.6%-23.9%] vs 2.5% for normal cervical length [interquartile range, 0%-5.5%], P=.001 and 6.6% [interquartile range, 0%-13.4%] vs 0% for normal cervical length [interquartile range, 0%-2.8%], P=.014, respectively). Within subgroup analyses, cervical length was inversely proportional to percentage of observed short-bursts (P=.013) and bursts (P=.014). Subjects with short cervical length and history of preterm birth had higher burst percentages (12.8% [interquartile range, 9.0%-15.7%]) than those with short cervical length and no history of preterm birth (3.3% [interquartile range, 0%-5.0%], P=.003)., Conclusion: Short-burst and burst uterine electromyography signals are observed more frequently in mid-trimester patients with short cervical lengths. This relationship provides insight into abnormal myometrial activation in the mid-trimester and offers a plausible biophysiological link to cervical shortening., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: To estimate the ability of a combination of first-trimester markers to predict preterm preeclampsia in nulliparous women., Methods: We conducted a prospective cohort study of nulliparous women with singleton gestations, recruited between 11 0 and 13 6 weeks gestation. Data on the following were collected: maternal age; ethnicity; chronic diseases; use of fertility treatment; body mass index; mean arterial blood pressure (MAP); serum levels of pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), alpha fetoprotein (AFP), free beta human chorionic gonadotropin (ß-hCG); and mean uterine artery pulsatility index (UtA-PI). We constructed a proportional hazard model for the prediction of preterm preeclampsia selected based on the Akaike information criterion. A receiver operating characteristic curve was created with the predicted risk from the final model. Our primary outcome was preterm preeclampsia and our secondary outcome was a composite of preeclampsia, small for gestational age, intrauterine death, and preterm birth., Results: Among 4659 nulliparous women with singleton gestations, our final model included 4 variables: MAP MoM, log 10 PlGF MoM, log 10 AFP MoM and log 10 UtA-PI MoM. We obtained an area under the curve of 0.84 (95% CI 0.75-0.93) with a detection rate of preterm preeclampsia of 55% (95% CI 37%-73%) and a false-positive rate of 10%. Using a risk cut-off with a false-positive rate of 10%, the positive predictive value for our composite outcome was 33% (95% CI 29%-37%)., Conclusions: The combination of MAP, maternal serum PlGF and AFP, and UtA-PI are useful to identify nulliparous women at high risk of preterm preeclampsia but also at high risk of other great obstetrical syndromes., (Copyright © 2020 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objective: First trimester screening is essential to preeclampsia (PE) prevention. Fetal Medicine Foundation (FMF) model combined maternal characteristics with mean arterial pressure (MAP), uterine artery pulsatility index (UtAPI) and placental growth factor (PlGF) to estimate risk. High detection rate (DR) was observed in Asia. The study aims to evaluate performance of screening in Taiwan., Materials and Methods: This was a prospective and non-interventional study between January, 2017 and June, 2018. Data was collected from 700 pregnant women at 11 +0 -13 +6 gestational week. Maternal characteristics were recorded. MAP, UtAPI and PlGF were measured and converted into Multiple of the Median (MoM). Patient-specific risks were calculated with FMF model. Performance of screening was examined by ROC curve and DR., Results: 25 women (3.57%) contracted PE, including 8 with preterm PE (1.14%). In preterm PE, mean MoM of MAP and UtAPI were higher (1.096 vs 1.000; 1.084 vs 1.035). Mean MoM of PlGF was lower (0.927 vs 1.031). DR in preterm PE achieved 12.5%, 50.0%, 50.0% and 62.5% at false-positive rate (FPR) of 5%, 10%, 15% and 20%., Conclusion: FMF model showed high DR for PE in Taiwan. Integration of PE and Down screening could set up a one-step workflow., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To analyze if sFlt-1/PlGF ratio is more useful than other parameters at diagnosis of early-onset (<34 weeks) preeclampsia (PE) in the prediction of delivery within 48 h and adverse maternal and perinatal outcomes., Method: Observational retrospective study of a cohort of 76 singleton pregnancies with early-onset PE and expectant management. The predictive value of sFlt-1/PlGF ratio, blood pressure, proteinuria, creatinine, liver enzymes and platelets at diagnosis for delivery < 48 h and adverse outcomes was determined., Results: Maternal and perinatal adverse outcomes occurred in 25/76 (32.9%) cases and 13/69 (18.8%) livebirths, respectively. Areas under the curve (AUC) for sFlt-1/PlGF ratio were 0.59 (95%CI 0.42-0.75) and 0.75 (95%CI 0.62-0.88) for maternal and perinatal complications, respectively. Mean (standard deviation) time to delivery for a sFlt-1/PlGF ratio > 655 vs. ≤ 655 was of 4.4 (7.5) vs. 12.1 (9.3) days, p < 0.01. Relative risk for delivery within 48 h for a sFlt-1/PlGF ratio > 655 was 5.3 (95% confidence interval 2.7-10.6), p < 0.01., Conclusions: sFlt-1/PlGF ratio > 655 at diagnosis was associated with a 5-fold increased risk of delivery in ≤ 48 h. None of the parameters were good predictors of adverse maternal or perinatal outcomes., (Copyright © 2020 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Introduction: Preeclampsia (PE) is one of the most common causes of major maternal and fetal adverse events including mortality and preterm birth Grill et al. (2009). The neutrophil-to-lymphocyte ratio (NLR) and other hematologic indexes of systemic inflammation have been investigated in patients with PE for the prediction of the severity or presence of the disease. Despite these studies, we found no trials investigating the relationship between NLR and fetal outcomes in PE patients. In this study, we aimed to investigate the relationship between NLR and fetal outcomes., Methods: We retrospectively analyzed the demographic data and laboratory tests to determine the NLR of 175 pregnant women with severe PE admitted to our clinic between January 2015 and December 2018., Results: NLR in the first (2.4 ± 1.1 vs 2.9 ± 1.4, P = 0.18) and second trimesters (3.6 ± 0.7 vs 3.8 ± 1.3, P = 0.25) were not different between the groups, but third trimester NLR was significantly higher in patients with fetal loss (6.5 ± 5.4 vs 4.2 ± 2.7, P = 0.009). The area under the receiver operating characteristic curve for NLR in the third trimester was 0.66 and NLR > 3.9 predicted fetal loss with a sensitivity of 75% and a specificity of 61% (0.684, 95% confidence interval 0.48-0.83, P = 0.05)., Conclusion: We demonstrated that third trimester NLR is associated with fetal loss in patients with severe PE., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To assess the diagnostic accuracy and cost-effectiveness of fetal fibronectin (fFN) and cervical phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) tests, individually and in combination, to predict preterm delivery within 48 hours, 7 days and 14 days in symptomatic women., Method: We selected women in Victoria, British Columbia, who presented between January 2008 and December 2017 at <34 weeks gestation at intermediate risk for labour (intact membrane, cervical dilatation <3 cm, and >6 contractions per hour). We calculated sensitivity, specificity, and positive and negative predictive values (PPV, NPV) for independent and concurrent testing and conducted a cost-effectiveness analysis to ensure appropriate test utilization., Results: We identified 2911 cases. Both fFN and phIGFBP-1 tests showed high and comparable NPV in predicting risk of delivery within 48 hours, 7 days and 14 days (fFN: 99.3%, 98.5% and 97.3%; phIGFBP-1: 98.8%, 97.9% and 96.1%). In 1976 cases, samples for fFN and phIGFBP-1 tests were collected and analyzed concurrently. Concurrent analysis increased specificity (90.8%, 91.4%, and 91.8%) and PPV (11.8%, 19.8% and 24.2%). Independently, both tests had comparable sensitivity, while the fFN test had higher specificity. Concurrent testing offered the highest PPV. The net gain in PPV comes with a clinically insignificant net loss (<1%) in NPV when compared with either of the tests individually., Conclusion: Clinical usefulness of PPV for either test is limited. Routine concurrent testing comes with additional costs, and fFN has additional collection requirements. Point-of-care phIGFBP-1 testing has proven to be cheaper, simpler, and equally effective. Ordering physicians should be provided with education on how to interpret test results and should have protocols to guide clinical decision making., (Copyright © 2020 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Background: Spontaneous preterm birth is a leading cause of neonatal morbidity and mortality. Early identification of at-risk women by reliable screening tests could reduce the spontaneous preterm birth rate, but conventional methods such as obstetrical history and maternal cervical length screening identify only a minority of spontaneous preterm birth cases. Cervicovaginal fluid might prove to be a useful, readily available biological fluid for identifying spontaneous preterm birth biomarkers., Objective: The objective of the study was to identify cervicovaginal fluid biomarkers of early spontaneous preterm birth in a high-risk cohort of pregnant women with a history of spontaneous preterm birth using targeted and shotgun proteomic analyses., Study Design: A nested case control study (cases were spontaneous preterm birth <34 weeks in the current pregnancy; controls were spontaneous labor and delivery at 39-41 weeks) was performed using cervicovaginal fluid samples collected at 3 study visits (10 0/7 to 18 6/7 weeks, 19 0/7 to 23 6/7 weeks, and 28 0/7 to 31 6/7 weeks). All participants had a history of at least 1 prior spontaneous preterm birth. Targeted proteomic analysis was performed using a stable isotope-labeled proteome derived from endocervical and vaginal mucosal cells. This served as a standard to quantitate candidate protein levels in individual cervicovaginal fluid samples from the second and third study visits using liquid chromatography-multiple reaction monitoring mass spectrometry. The ratio of endogenous peptide area/stable isotope-labeled proteome-derived peptide area was used to measure levels of 42 peptides in 22 proteins. To maximize biomarker discovery in the cervicovaginal fluid samples, shotgun proteomic analysis also was performed utilizing liquid chromatography and ion trap mass spectrometry. A validation study was performed in second-trimester cervicovaginal fluid samples from an independent study group (12 spontaneous preterm birth cases, 19 term delivery controls) using enzyme-linked immunosorbent assay for 5 proteins expressed at higher levels in spontaneous preterm birth cases compared with controls in targeted or shotgun proteomic analyses., Results: For targeted proteomics, cervicovaginal fluid samples from 33 cases and 32 controls at 19 0/7 to 23 6/7 weeks and 16 cases and 14 controls at 28 0/7 to 31 6/7 weeks from the same pregnancies were analyzed. When samples were compared between cases and controls, the relative abundance of 5 proteins was greater (P = .02-.05) in cases at both visits, while the relative abundance of 1 protein was lower (P = .03) in cases at both visits. For shotgun proteomics analyses, cervicovaginal fluid samples were pooled for 9 spontaneous preterm birth cases and 9 term delivery controls at each study visit. Shotgun proteomics yielded 28 proteins that were detected at levels >2 times higher and 1 protein that was detected at a level <0.5 times lower in spontaneous preterm birth cases compared with controls at all 3 study visits. Validation enzyme-linked immunosorbent assay for 5 proteins that were detected at higher levels in cervicovaginal fluid samples from spontaneous preterm birth cases compared with term delivery controls in proteomics analyses did not demonstrate statistically significant differences between spontaneous preterm birth cases and controls., Conclusions: Potential biomarkers of spontaneous preterm birth were identified by targeted and shotgun proteomics analyses in cervicovaginal fluid samples from high-risk, asymptomatic women. Many of the proteins detected at higher levels in cervicovaginal fluid samples from spontaneous preterm birth cases are extracellular matrix proteins and/or regulate cell membrane physiology. These proteins have substantial biological interest, but validation enzyme-linked immunosorbent assay for 5 of these proteins did not yield clinically useful biomarkers for spontaneous preterm birth., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: We aimed to determine whether inhibin A could be a reliable and accurate predictor of preterm birth, and discuss the possible pathogenic processes of inhibin A leading to preterm birth., Methods: A retrospective cohort study was conducted on consecutive singleton pregnant women who underwent the second-trimester quad screen test at a gestational age of 15-20 weeks at Keelung Chang-Gung Memorial Hospital from March 2011 to May 2015. Data including maternal characteristics and pregnancy outcomes were collected from an electric medical record database. Data regarding pregnancy terminations before a gestational age of 24 weeks and regarding pregnancies that involved chromosomal or congenital anomalies were excluded from this analysis. One-way analysis of variance was used to compare second-trimester α-fetoprotein, human chorionic gonadotropin, unconjugated estriol, and inhibin A in women with preterm deliveries versus those with term deliveries., Results: Although a total of 935 women with singleton pregnancies were enrolled, pregnancy outcome and complete maternal data were obtained from only 770 (82.3%)of them. In total, 687 (89.2%) women delivered at or after 37 weeks of gestation and 83 (10.8%) women delivered before 37 weeks of gestation. The results showed that the inhibin A level was significantly increased in the preterm labor group (p = 0.009). A cutoff inhibin A value above 2.25 was identified statistical significantly in the preterm labor group., Conclusions: From our results, an inhibin A level above 2.25 multiples of the median in the quad screen test may be associated with preterm labor afterward. Closely monitoring for uterine contractions or cervical length measurement in the second trimester may be indicated in patients with unexplained elevated inhibin A levels., (Copyright © 2019 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Objective: To compare characteristics and outcomes of women with chronic hypertension (cHTN) between those with normal and abnormal plasma angiogenic profiles., Study Design: This secondary analysis explored associations between angiogenic markers soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) drawn prior to delivery among women with history of cHTN who were enrolled between 22 and 41 weeks. Patients were divided into two groups based on sFlt1/PlGF ratio, namely low sFlt1/PlGF (<85) and high sFlt1/PlGF (≥85) ratio., Results: Of the 115 patients, 76% were African American. Compared to women with low sFlt1/PlGF (n = 78), patients with high sFlt1/PlGF (n = 37) had higher median antenatal blood pressures (systolic mmHg 179 vs 155; diastolic 106 vs 91), lower gestational age at delivery (34.7 vs 38.2 weeks), lower birthweight (1940 vs 3103 g), and a higher prevalence of preterm delivery <34 (40.5% vs 7.7%) and <37 weeks (64.9% vs 20.5%), all p < 0.001. Importantly, more women with high sFlt1/PlGF had a diagnosis of superimposed preeclampsia (62.2% vs 26.9%, p = 0.003), preeclampsia with severe features (59.5% vs 20.5%, p < 0.0001), maternal adverse outcomes (24.3% vs 3.9%, p = 0.002), neonatal intensive care unit admissions (71.9% vs 40.8%; p = 0.003), severe postpartum hypertension (67.6% vs 38.5%, p = 0.01) and longer hospital stays (median 6.0 vs 4.5 days, p = 0.003)., Discussion: In contrast to patients with a low ratio, high sFlt1/PlGF is characterized by an increased risk of maternal adverse outcomes and prematurity. Incorporation of angiogenic biomarkers while managing cHTN may improve accuracy of early identification of adverse outcomes to improve outcomes., (Copyright © 2020 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Preterm delivery contributes to an increased risk of fetal and maternal death as well as several health deficiencies, thereby requiring special care and treatment that result in high financial costs. It is therefore of key importance to diagnose preterm delivery in advance in order to avoid or minimize its undesirable consequences. This paper proposes a novel method for non-invasive diagnosis of preterm delivery based on the classification of electrohysterography (EHG) signals. First, the EHG signal, which is related to the electrical activity of uterine muscles is recorded from the maternal fundus using surface electrodes. Then, the signal is sliced into frames for spectral analysis. Next, spectral analyses of the individual EHG signal frames are carried out and centroid frequencies of the frames are computed, establishing the elements of a feature vector that represents the time-varying spectral content of the EHG signal. Finally, this feature vector is employed for the classification of the underlying EHG signal for term-preterm diagnosis. The efficiency of the proposed approach is evaluated and compared with representative methods from the literature. Our results demonstrate that the proposed approach exhibits superior performance over other methods., 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 © 2020 Elsevier Ltd. All rights reserved.)

Objective: The objective was to provide an update of progress made over time (including personal reflection) of our attempts to reduce the mortality and morbidity associated with spontaneous preterm labour that leads to preterm birth., Methods: An experienced and evidence based approach was taken to provide an overview of progress made over a generation (∼40 years) in our understanding of spontaneous preterm labour., Results: It is evident that we have made significant progress in our understanding of the aetiology, the measurement of the burden, the basic science, systems biology and mechanical pathways of the preterm parturition syndrome. We have better ways of predicting, preventing and managing spontaneous preterm labour than existed a generation ago., Conclusions: The profile of spontaneous preterm labour that leads to preterm birth, thanks to organisations such as the March of Dimes, WHO and PREBIC is much more evident than before. However, while we have come a long way, we must not be complacent, and clinicians and basic scientists must continue to work in harmony, while recruiting and encouraging young investigators to join the effort to improve survival and handicap in what is one of the Great Obstetric Syndromes., (Copyright © 2019. Published by Elsevier Ltd.)

The prediction or early diagnosis of maternal complications is challenging mostly because the main conditions, such as preeclampsia, preterm birth, fetal growth restriction, and gestational diabetes mellitus, are complex syndromes with multiple underlying mechanisms related to their occurrence. Limited advances in maternal and perinatal health in recent decades with respect to preventing these disorders have led to new approaches, and "omics" sciences have emerged as a potential field to be explored. Metabolomics is the study of a set of metabolites in a given sample and can represent the metabolic functioning of a cell, tissue or organism. Metabolomics has some advantages over genomics, transcriptomics, and proteomics, as metabolites are the final result of the interactions of genes, RNAs and proteins. Considering the recent "boom" in metabolomic studies and their importance in the research agenda, we here review the topic, explaining the rationale and theory of the metabolomic approach in different areas of maternal and perinatal health research for clinical practitioners. We also demonstrate the main exploratory studies of these maternal complications, commenting on their promising findings. The potential translational application of metabolomic studies, especially for the identification of predictive biomarkers, is supported by the current findings, although they require external validation in larger datasets and with alternative methodologies.

Preterm birth, defined as birth occurring prior to 37 weeks gestation, is a serious obstetric problem accounting for 11% of pregnancies worldwide. It is associated with significant neonatal morbidity and mortality. Predictive tests for preterm birth are incredibly important, given the huge personal, economic, and health impacts of preterm birth. They can provide reassurance for women who are unlikely to deliver early, but they are also important for highlighting those women at higher risk of premature delivery so that we can offer prophylactic interventions and help guide antenatal management decisions. Unfortunately, there is unlikely to be a single test for predicting preterm birth, but a combination of tests is likely to improve clinical prediction. This review explores the clinical utility of the currently marketed predictive tests for preterm birth in both singleton and multiple pregnancies, as well as discussing novel predictive tests that may be useful in the future., (© 2018 Published by Elsevier Ltd.)

Background: Placental alpha microglobulin-1 and phosphorylated insulin-like growth factor-binding protein-1 have been studied in patients at risk for preterm birth with signs and symptoms of preterm labor. However, a direct comparison between these 2 biomarkers, alone or in combination with cervical length measurement with an adequate sample size, has been lacking to date., Objective: The purpose of this study was to compare the placental alpha microglobulin-1 test and the phosphorylated insulin-like growth factor-binding protein-1 test alone and in combination with cervical length measurement for the prediction of imminent spontaneous preterm birth of testing in pregnant women with symptoms of preterm labor in a tertiary care setting., Study Design: Four hundred three patients with intact amniotic membranes and cervical dilation ≤3 cm, without recent intercourse or cerclage, between gestational weeks of 20 +0 and 36 +6 were recruited prospectively from 3 international centers. Placental alpha microglobulin-1 and phosphorylated insulin-like growth factor-binding protein-1 tests were conducted before cervical length measurement via transvaginal ultrasound scanning. Caregivers were blinded to the biomarker test results. Medically indicated deliveries within 14 days of testing were excluded. Standard performance statistics with 95% confidence intervals were calculated and compared based on pairwise estimates from a generalized model., Results: Of 403 subjects who were enrolled in the study cohort, 94% (383/403 women) met the inclusion criteria. Median gestational age and cervical length at presentation were 30 +5 weeks and 27 mm, respectively; 6.8% women (26/383 women) had spontaneous birth ≤7 days from testing. The placental alpha microglobulin-1 test was positive in 7.8% of the women (30/383 women); the phosphorylated insulin-like growth factor-binding protein-1 test was positive in 29.5% women (113/383 women). Positive predictive value for placental alpha microglobulin-1, phosphorylated insulin-like growth factor-binding protein-1, and cervical length <25 mm for the prediction of spontaneous preterm birth in the overall cohort was 60.0% (18/30 women), 18.6% (21/113 women), 11.8% (18/152 women), respectively. The negative predictive value was 97.7% (345/353 women), 98.2% (265/270 women), 96.5% (223/231 women), respectively. The prevalence of spontaneous preterm birth in this group was 6.8% (26/383 women). The positive likelihood ratios were 20.6, 3.1, and 1.8, respectively. The negative likelihood ratio were 0.3, 0.3, and 0.5, respectively. Positive predictive values for placental alpha microglobulin-1 and phosphorylated insulin-like growth factor-binding protein-1 tests in patients with cervical length shortening of 15-30 mm for the prediction of spontaneous preterm birth were 60.9% (14/23 women) and 28.1% (16/57 women), respectively. The negative predictive values were 97.1% (168/173 women) and 97.8% (136/139 women), respectively. The prevalence of spontaneous preterm birth in the 15-30 mm cohort was 9.7% (19/196 women). The positive likelihood ratios were 14.5 and 3.6, respectively. The negative likelihood ratios were 0.3 and 0.2, respectively., Conclusion: Placental alpha microglobulin-1 is significantly more specific than phosphorylated insulin-like growth factor-binding protein-1 for the prediction of spontaneous preterm birth ≤7 days (P<.0001), whereas both tests have comparable sensitivity. In patients with cervical length 15-30 mm, although placental alpha microglobulin-1 has a significantly higher positive predictive value and specificity compared with phosphorylated insulin-like growth factor-binding protein-1 for the prediction of spontaneous preterm birth at ≤7 days (P<.01), both tests have a comparable sensitivity and negative predictive value. In conclusion, placental alpha microglobulin-1 is a better predictor of imminent spontaneous preterm birth when compared with phosphorylated insulin-like growth factor-binding protein-1 alone or in combination with cervical length measurement. In patients with shortening of cervical length of 15-30 mm, the placental alpha microglobulin-1 test is a significantly better predictor of imminent spontaneous preterm birth within 7 days of testing than is phosphorylated insulin-like growth factor-binding protein-1., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cervical length (CL) measured by transvaginal ultrasound examination (TVUE) best identifies the risk for preterm birth (PTB). It identifies women at risk who can benefit from corticosteroids or in utero transfer. Early screening improves effectiveness of tocolysis. It reduces iatrogenicity and cost. In preterm premature rupture of membranes (PPROM), CL is devoid of infectious risk and predicts duration of the latency phase but not the risk of perinatal sepsis. Asymptomatic women at risk should be screened at a 2-week interval starting from 16 to 18 weeks, up to 24 weeks. CLs <10th centile are at risk of PTB, especially with decrease in CL after 16 weeks. Repeat ultrasound improves predictive values. Stable CL calls for term delivery. Funneling does not improve predictivity of CL. In twin pregnancies, CL reduces unnecessary interventions. In symptomatic women, fetal fibronectin performs less than CL. Its combination with inconclusive CL has not emerged productive through randomized controlled trials (RCTs), and studies with homogeneous management for preterm labor (PTL) suggest that up to 15% of unjustified hospitalizations and treatment could be avoided., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: To investigate whether the levels of angiogenic factors in cord blood are associated with the development of bronchopulmonary dysplasia (BPD) in preterm infants with maternal preeclampsia., Study Design: This retrospective cohort study included 199 singleton infants (gestational age < 32 weeks), including the preeclampsia group (59 infants) with severe/moderate BPD (24 infants) or no/mild BPD (35 infants) and the no preeclampsia group (140 infants)., Main Outcomes Measures: The levels of soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin, and placental growth factor (PlGF) in cord blood were measured and compared among the study groups., Results: The soluble endoglin level and the ratio of (sFlt-1 + soluble endoglin) to PlGF were significantly higher in the preeclampsia group than in the no preeclampsia group (P < .05). Among preterm infants with maternal preeclampsia, both of these parameters were also significantly higher in the severe/moderate BPD group than the no/mild BPD group (P < .05). Receiver operator curve analysis revealed that increased cord blood soluble endoglin was predictive of severe or moderate BPD in preterm infants with maternal preeclampsia (area under the curve 0.73). Gestational age (adjusted odds ratio [OR] 0.25; P < .001) and high soluble endoglin level in cord blood (>3420 pg/mL) (adjusted OR 11.9; P = .006) were significant risk factors for the development of severe or moderate BPD in the preeclampsia group according to multivariate logistic regression analysis., Conclusion: Increased cord blood soluble endoglin is associated with the development of severe or moderate BPD in preterm infants with maternal preeclampsia., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objectives: To better understand the effects of maternal age on birth outcomes among preeclampsia (PE) patients, we examined the rates of preterm birth, low birthweight, and small for gestational age (SGA) among different age groups and explored whether maternal age was associated with those adverse outcomes., Study Design: This is a multicenter retrospective study. Data from 1128 PE patients, including 580 with early onset PE and 548 with late onset PE, were analyzed., Main Outcome Measures: Maternal age was categorized into three groups: <25, 25-34, and ≥35 years. The outcome variables were preterm birth (<37 weeks; subgroups: <28 weeks, 28-33 weeks, and 34-36 weeks), low birthweight (<2500 g; subgroups: <1500 g and <1000 g), and SGA. Logistic regression was used to analyze the associations between maternal age groups and outcomes., Results: In early onset PE, compared with maternal age 25-34 years, maternal age ≥35 years was associated with elevated risk for preterm delivery before 28 weeks, and maternal age <25 years was associated with elevated risk for low birthweight and SGA. When the analysis was restricted to women who underwent cesarean section, elevated risks for preterm birth and/or low birthweight were observed for women younger than 25 years in both early and late onset PE., Conclusions: Among women with PE, maternal age <25 years could add risk to preterm birth and/or low birthweight. For women with early onset PE, maternal age ≥35 years is a risk factor for preterm delivery before 28 weeks., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of the study was to determine the relationships between short cervical length (CL) and levels of cervical fluid neutrophil elastase (NE), secretory leukocyte protease inhibitor (SLPI), and interleukin 8 (IL-8) in the second trimester of pregnancy of women who underwent ultrasound-indicated cervical cerclage., Materials and Methods: CL of <25 mm or cervical funneling were included in the short CL group (n = 26) and the normal CL group (n = 22) included women who had CL of ≥25 mm and had no cervical funneling in women between 17 + 0 and 24 + 6 weeks of gestation. Levels of NE, SLPI, and IL-8 were measured by using enzyme-linked immunosorbent assay kits. Mann-Whitney U tests and Spearman's correlation analysis were used for statistical analyses., Results: Compared with the normal CL group, the short CL group had significantly higher median NE levels (P < 0.001) and higher, though not significant, median IL-8 levels by approximately three times (2107.0 vs. 798.3 pg/mL, P = 0.132). The median SLPI levels in cervical fluid was similar between the two groups (107.6 vs. 103.2 ng/mL, P = 0.499). Short CL had a significant correlations with cervical fluid NE levels (r = -0.475, P = 0.001)., Conclusion: Increased cervical fluid NE associated with cervical shortening in second trimester of pregnancy, whereas cervical fluid SLPI had constant levels., (Copyright © 2018. Published by Elsevier B.V.)

Objective: Small studies suggest that fetal sex alters maternal inflammation. We examined the association between fetal sex, preeclampsia and circulating maternal immune markers., Methods: This was a secondary data analysis within a nested case-control study of 216 preeclamptic women and 432 randomly selected normotensive controls from the Collaborative Perinatal Project. All women had singleton, primiparous pregnancies without chronic health conditions. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for associations between female fetal sex and preeclampsia. Outcomes included preeclampsia, preterm preeclampsia (<37 and <34 weeks), and normotensive preterm birth <37 weeks. Associations between female fetal sex and immune markers [interleukin (IL)-6, IL4, IL5, IL12, IL10, IL8, IL1-beta, interferon (IFN)-gamma, tumor necrosis factor (TNF)-beta, and transforming growth factor-beta] were examined using a statistical method developed for large proportions of censored biomarker data. Models were adjusted for maternal age, race, body mass index, and smoking., Results: Women with early preterm preeclampsia (<34 weeks) had higher odds of having a female fetus (OR adj. 3.2, 95% CI 1.1-9.6) and women with normotensive preterm birth had lower odds (OR adj. 0.5, 95% CI 0.3-0.9). Female fetal sex was associated with lower first trimester pro-inflammatory IFNγ and IL-12 but higher second trimester pro-inflammatory IL1β and TNFβ, anti-inflammatory IL4r, and regulatory cytokines IL5 and IL10. Female fetal sex was associated with higher postpartum IL10 in preeclamptic women only., Conclusions: We identified sexual dimorphism in maternal inflammation. Longitudinal studies are needed to determine if fetal sex impacts the maternal immune milieu across pregnancy., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Despite considerable effort aimed at decreasing the incidence of spontaneous preterm birth, it remains the leading cause of perinatal morbidity and mortality. Screening strategies are imperfect. Approaches used to identify women considered by historical factors to be low risk for preterm delivery (generally considered to be women with singleton pregnancies without a history of a previous preterm birth) as well as those at high risk for preterm birth (those with a previous preterm birth, short cervix, or multiple gestation) continue to evolve. Herein, we review the current evidence and approaches to screening women for preterm birth, and examine future directions for clinical practice. Further research is necessary to better identify at-risk women and provide evidence-based management., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: To review (1) the use of ultrasonographic-derived cervical length measurement in predicting preterm birth and (2) interventions associated with a short cervical length., Outcomes: Reduction in rates of prematurity and/or better identification of those at risk, as well as possible prevention of unnecessary interventions., Evidence: Published literature was retrieved through searches of PubMed and The Cochrane Library up to December 2009, using appropriate controlled vocabulary and key words (preterm labour, ultrasound, cervix, incompetent cervix, transvaginal, transperineal, cervical length, fibronectin). Results were restricted to general and systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies., Values: The evidence and this guideline were reviewed by the Diagnostic Imaging Committee and the Maternal Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada, and the recommendations were made according to the guidelines developed by The Canadian Task Force on Preventive Health Care (Table 1)., Benefits, Harms, and Costs: Preterm birth is a leading cause of perinatal morbidity and mortality. Use of the ultrasonographic technique reviewed in this guideline may help identify women at risk of preterm birth and, in some circumstances, lead to interventions that may reduce the rate of preterm birth., Sponsors: The Society of Obstetricians and Gynaecologists of Canada SUMMARY STATEMENTS: RECOMMENDATIONS., (Copyright © 2018. Published by Elsevier Inc.)

Objective: Examine the frequency with which the most accepted indicators for delivery in pre-eclampsia are used in a population with predominantly late-onset (birth > 32 weeks) pre-eclampsia (PE)., Methods: Retrospective cohort study using the St George Public Hospital (SGH) Hypertension in Pregnancy database. Demographic, pregnancy, and outcome details were extracted and verified by comparison with data collection sheets., Results: From 2001 to 2013, 908 women (970 babies) with PE were included, of which a subgroup of 303 women (33%) had clearly delineated delivery triggers available. This subgroup of women had similar demographic and outcome characteristics to the total PE population. In this group, the most common maternal trigger for delivery apart from gestational age 37+ weeks was difficult to control/severe hypertension (114 cases, 38%) and the most common fetal trigger intrauterine growth restriction (IUGR: 14 cases, 4%). 78 (35%) of term women had no specific delivery trigger other than gestation. A primary maternal trigger and/or associated complication was slightly more common in those delivering <37 weeks vs 37+ weeks (52 vs 38%, p = .03), while a fetal or combined maternal/fetal complication was over four times more common in preterm women (25 vs 6%, p < .001)., Conclusion: In our population of predominantly late-onset PE, maternal triggers for delivery (predominantly severe hypertension) far outweigh fetal triggers (predominantly IUGR). Fetal and mixed indicators for delivery were relatively more common in women delivering preterm, possibly reflecting the severity of placental dysfunction in this subgroup., (Copyright © 2017 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background: Inflammasomes regulate activation of caspase-1, which cleaves and activates interleukin (IL)-1β and IL-18, the cytokines that trigger pro-inflammatory and antimicrobial responses. There is very little known about inflammasome function in the subsets of monocytes (MO) isolated from preterm neonates born extremely and very prematurely., Methods: A group of 76 very low birth weight patients without early-onset sepsis was divided into extremely preterm (<28 gestational week) or very preterm (28-32 gestational week) neonates. The first blood sample was collected on the 5th day of life (5th DOL) to analyse MO subsets as well as the intracellular IL-1β expression and supernatant concentration of IL-1β and IL-18. Secondary blood samples were collected within 24h of late-onset sepsis (LOS) development and analysed as above., Results: On the 5th DOL, the extremely preterm neonates were characterized by a significantly higher absolute count of MO, in particular in the classical and intermediate subsets, as compared to the very preterm group. The counts of the intermediate and non-classical MO subsets increased during LOS in all neonates. We did not observe significant differences in the intracellular IL-1β expression between the analysed groups. Furthermore, the levels of the analysed cytokines in the MO supernatants were comparable between the extremely and very preterm neonates on the 5th DOL. Finally, a higher level of IL-18 was observed in the supernatant of the extremely preterm group during LOS., Conclusions: During LOS, extremely preterm neonates excrete a higher level of IL-18 cytokines compared to very preterm neonates. Further studies are required to determine whether this observation is a result of a higher count of the circulating MO or is a true reflection of increased inflammasome function in this particular group of newborns., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Stillbirth is one of the most distressing complications of pregnancy and still occurs far too frequently. The rate of stillbirth has been decreasing worldwide but room for improvement remains even in high-income countries. Risk factors for stillbirth have been identified in an effort to detect those women at increased risk. However, risk factors are non-specific and do not identify most stillbirths. Strategies employed to screen the general population such as assessment of fetal activity, fetal growth screening and biomarkers have also been used to identify increased risk for stillbirth. As with clinical risk factors, these methods are non-specific. Interventions to prevent stillbirth include antenatal testing of high-risk women, ultrasonographic assessments of fetal growth and Doppler velocimetry as well as iatrogenic preterm or term delivery. Additional research into the role of these interventions and better identification of those at high risk for stillbirth will help to achieve further stillbirth reduction., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Describe tools designed to predict preterm birth in asymptomatic high-risk pregnancy and determine their predictive value., Methods: The PubMed database, the Cochrane Library and the recommendations from the French and foreign obstetrical societies or colleges have been consulted., Results: Obstetric history particularly spontaneous preterm birth identifies a population at risk for preterm birth for the current pregnancy (LE3). This risk is related to the number of prior preterm birth and is even higher than the term of the prior event is more premature and that the event concerns the last pregnancy (LE3). The literature data are insufficient to recommend systematic cervical examination at each prenatal visit in asymptomatic high-risk pregnancy (multiple pregnancy, uterine malformations, history of spontaneous preterm birth, excisional cervical procedure or at least two voluntary first trimester abortion) (professional consensus). Regular recording of uterine activity and home visits for asymptomatic high-risk pregnancy did not predict nor reduce the risk of preterm birth (LE2) and are not recommended (grade B). In asymptomatic high-risk pregnancy, ultrasonographic measurement of cervical length estimates the risk of preterm birth (LE2). Shorter is the cervical length higher is the risk of preterm birth (LE3). In asymptomatic patient with prior preterm birth, ultrasonographic measurement of cervical length estimates the risk of preterm birth (LE2). The strategy of ultrasound indicated cerclage are discussed in dedicated chapter. The measurement of cervical length by transvaginal ultrasonography in asymptomatic pregnancy with uterine malformation, a history of cervical treatment, at least two voluntary abortions or having a multiple pregnancy would estimate the risk of preterm birth (LE3). A shortening of more than 10% of the cervical length at 3-week interval is associated with an increased risk of preterm birth (LE3). Systematic detection of fetal fibronectin is not recommended in asymptomatic high-risk population (grade C). The combination of ultrasound measurement of cervical length and fetal fibronectin detection improves modestly the prediction of preterm birth (LE3). However, literature data are insufficient to recommend routine measurement of cervical length by transvaginal ultrasonography during surveillance ultrasounds and/or detection of fetal fibronectin because this policy has never demonstrated its interest in preventing preterm birth and in the reduction of neonatal morbidity and mortality (professional consensus)., Conclusion: Several predictive tools are described to define the risk of preterm birth but there is no evidence to date of the effectiveness of systematic screening strategy on the prevention of prematurity in asymptomatic high-risk population, except the ultrasound measurement of the cervical length in the population of patients having had a prior preterm birth., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Objectives: To evaluate the predictors of spontaneous preterm birth in case of preterm labor., Materials and Methods: Literature search in Medline and Cochrane databases and recommendations of international societies. Selection of studies in symptomatic women (with preterm labor)., Results: Preterm labor is defined as a clinical situation occurring between 22 and 36 weeks + 6 days, in which cervical changes are observed associated with uterine contractions, evolving spontaneously or not to preterm delivery (Professional consensus). Uterine contractions can be detected by the cardiotocometry and by the patient herself. Uterine contractions frequency does not reliably predict spontaneous preterm birth (NP3). Cervical modifications may be appreciated by ultrasonographic measurement of cervical length and vaginal examination (Bishop score). Cervical length is significantly correlated with the risk of spontaneous preterm birth (NP1). The 15 and 25mm thresholds are the most relevant to respectively predict and rule out spontaneous premature birth at 48hours and 7 days (professional consensus). In symptomatic patients, routine ultrasonographic measurement of cervical length at admission is not associated with a significant reduction of spontaneous preterm birth rate (NP3). Clinical evaluation of the cervix (Bishop score) by vaginal examination is an effective parameter for the prediction of preterm birth (NP2). The higher the Bishop score, the higher the risk of preterm birth (NP3). It is not possible to recommend the use of a tool more than another (cervix ultrasound versus vaginal examination) in women experiencing preterm labor (grade B). However, due to the excellent negative predictive value of cervical ultrasound measurement and the lower interobserver variability, we suggest to perform a cervical ultrasonographic measurement before an in utero transfer for preterm labor (professional consensus). Screening for fetal fibronectin in the genital tract of patients with preterm labor has an excellent negative predictive value for predicting the absence of spontaneous preterm birth at 48hours and 7 days (NP2). Nevertheless, its use in symptomatic women is not associated with a reduction of preterm birth rate (NP2) and is therefore not recommended (professional consensus)., Conclusion: Predictors of preterm birth in women with preterm labor are effective but do not allow a reduction of the preterm birth rate. The high negative predictive value of these predictors (Bishop score, ultrasound measurement of the cervix, fetal fibronectin detection in the genital tract) is an asset in the choice of an appropriate management in women with preterm labor (in utero transfer or corticosteroids)., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

The ultrasonographic measurement of cervical length with a cutoff of 15mm is currently the best method to identify a group of asymptomatic women in the general population at risk of spontaneous preterm birth, especially among asymptomatic patients with a singleton pregnancy with no history of preterm birth. Cerclage and 17 alpha-hydroxyprogesterone caproate (17OHP-C) are ineffective to reduce the risk of preterm birth among asymptomatic patients with a short cervix in midtrimester. However, vaginal progesterone (200-mg capsules of micronized progesterone or gel containing 90mg progesterone) has been demonstrated effective in 2 large randomized trials to reduce the risk of preterm birth and possibly the composite morbidity and perinatal mortality associated among asymptomatic women with a short cervix in the general population screened by ultrasound of the cervix in midtrimester. Three cost-effectiveness analyses are converging to show that universal screening for cervical length with vaginal progesterone treatment seems to be cost-effective compared with no screening. However, it is too early to definitively conclude that universal screening is justified for several reasons: many women must be screened to prevent a relatively small number of preterm births. Moreover, the epidemiology of preterm delivery is such that the use of progesterone in asymptomatic women with a short cervix screened by ultrasound in midtrimester in the general population will not significantly reduce the prevalence of preterm births; there are no data comparing the effectiveness of universal ultrasound screening followed by vaginal progesterone treatment in case of short cervix versus no universal screening associated to a progesterone treatment in case of incidentally observed short cervix; the universal ultrasound screening may not produce the same results in practice than those observed in published randomized trials, due to population differences, "indication creep", or "stretching of the cutoff" defining the short cervix. Moreover, the implementation of unevaluated or not recommended treatments, such as bed rest, tocolytics, 17OHP-C or cerclage, can potentially cause unintended deleterious consequences and reduce the cost-effectiveness; the cost-effectiveness analyses evaluating universal screening for cervical length present uncertainties on critical variables, notably the short cervix prevalence and the progesterone efficacy. In conclusion, although the implementation of such a screening strategy can be considered by individual practitioners, this screening cannot be universally mandated., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Cervical length at midtrimester is a powerful predictor of preterm birth in twin gestations. However, given the fact that, in some cases, cervical shortening may become evident only later during the second trimester, it seems reasonable that serial monitoring of cervical length may improve the detection of preterm birth in women with twins. However, data in support of such a practice are limited and conflicting. The contradictory results may be related to the fact that in most of these studies, the analysis of the predictive value of serial measurements of cervical length was limited to data derived from only two sequential measurements of cervical length, while data on the predictive value of multiple (>2) measurements are scarce., Objective: We sought to determine whether serial measurements of cervical length can improve the prediction of preterm birth in asymptomatic women with twin gestations compared with a single measurement of cervical length at midgestation., Study Design: This was a retrospective cohort study of women with twin pregnancies followed up in a tertiary medical center from 2012 through 2014. All participants underwent routine measurement of cervical length at midgestation and every 2-3 weeks thereafter until 28-32 weeks. For each patient, cervical length was determined at the following time periods: 18+0 to 21+6 weeks (period 1, routine exam), 22+0 to 24+6 weeks (period 2), 25+0 to 27+6 weeks (period 3), and 28+0 to 32+0 weeks (period 4). Measurements of cervical length at periods 2-4 were analyzed in the form of either absolute length (in millimeters) or percent shortening relative to cervical length at period 1. The performance of a stepwise algorithm that incorporated serial measurements of cervical length for the prediction of preterm birth was compared to that achieved with a single measurement of cervical length at period 1., Results: Overall, 441 women with twin pregnancies who were eligible for the study underwent a total of 2374 cervical length measurements. The association of a short cervix (<10th percentile) with preterm birth at <32 weeks persisted in each of the 4 periods of gestation [odds ratio (95% confidence interval): 7.2 (3.1-16.5), 15.3 (6.4-36.7), 10.3 (4.4-24.3), and 23.1(8.3-64.1), respectively]. Compared with a single measurement of cervical length at midgestation (period 1), a stepwise algorithm integrating serial cervical length measurements from all 4 successive gestational age periods resulted in a significant increase in the area under the receiver operating characteristic curve (0.917 vs 0.613, P < .001). Similarly, when a target false-positive rate of 5% was used, the same stepwise algorithm was associated with a higher detection rate (69% vs 28%, P < .001), higher positive likelihood ratio (14.54 vs 5.12), and lower negative likelihood ratio (0.32 vs 0.76) for preterm birth at <32 weeks compared with a single measurement of cervical length at period 1., Conclusion: Integration of serial measurements of cervical length using a stepwise algorithm in asymptomatic women with twin gestations can improve the detection of women at risk of preterm birth. Prospective studies are needed to validate these findings, and to investigate whether improved risk assessment performance is sufficient to offset the additional costs associated with serial cervical length measurements., Competing Interests: statement: The authors report no conflict of interest., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: It has been shown that noninvasive uterine electromyography (EMG) can identify true preterm labor more accurately than methods available to clinicians today. The objective of this study was to evaluate the effect of body mass index (BMI) on the accuracy of uterine EMG in predicting preterm delivery., Materials and Methods: Predictive values of uterine EMG for preterm delivery were compared in obese versus overweight/normal BMI patients. Hanley-McNeil test was used to compare receiver operator characteristics curves in these groups. Previously reported EMG cutoffs were used to determine groups with false positive/false negative and true positive/true negative EMG results. BMI in these groups was compared with Student t test (p < 0.05 significant)., Results: A total of 88 patients were included: 20 obese, 64 overweight, and four with normal BMI. EMG predicted preterm delivery within 7 days with area under the curve = 0.95 in the normal/overweight group, and with area under the curve = 1.00 in the obese group (p = 0.08). Six patients in true preterm labor (delivering within 7 days from EMG measurement) had low EMG values (false negative group). There were no false positive results. No significant differences in patient's BMI were noted between false negative group patients and preterm labor patients with high EMG values (true positive group) and nonlabor patients with low EMG values (true negative group; p = 0.32)., Conclusion: Accuracy of noninvasive uterine EMG monitoring and its predictive value for preterm delivery are not affected by obesity., (Copyright © 2016. Published by Elsevier B.V.)

Purpose: The aim of this study is to investigate the effectiveness of placental strain ratio (SR) values measured by real-time sonoelastography (SE) in the second trimester in the prediction of spontaneous preterm birth (sPTB)., Methods: This study included 70 pregnant women who applied to our clinic for routine second-trimester screening. Placental SR measurements were performed with the SE method. Two different SR measurements were performed by taking two different tissues as references. The SR value measured when taking the rectus abdominis muscle as a reference was termed the muscle-to-placenta strain ratio (MPSR), while the SR value measured when taking subcutaneous tissue as a reference was termed the fat-to-placenta strain ratio (FPSR). Women whose gestational age at birth was less than 37 weeks 0 days were accepted as sPTB. The association between gestational age at birth and MPSR and FPSR was investigated. Receiver operating characteristics analysis was used to calculate the sensitivity and specificity of the elastographic outcomes., Results: There was a low-level negative correlation between MPSR and gestational age at birth (r=-0.300, P=.012) and there was a moderate-level negative correlation between FPSR and gestational age at birth (r=-0.513, P<.001). The multivariate linear regression analysis showed that the FPSR (β=0.609, P=.002) was the significant predictor for the sPTB., Conclusions: Our data indicate that the FPSR value measured with real-time SE in the second trimester of pregnancy may be effective in the prediction of sPTB., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Cell-free deoxyribonucleic acid (DNA) is increasingly being used to screen for fetal aneuploidy. The majority of fetal cell-free DNA in the maternal blood results from release from the syncytiotrophoblast as a result of cellular apoptosis and necrosis. Elevated levels of fetal cell-free DNA may be indicative of underlying placental dysfunction, which has been associated with preterm birth. Preliminary studies have demonstrated that fetal cell-free DNA is increased in pregnancies complicated by spontaneous preterm birth. There are limited data on the association between fetal cell-free DNA levels and fetal fraction and preterm birth in asymptomatic women in the first and second trimesters. Preliminary studies have failed to find an association between first-trimester cell-free DNA levels and preterm birth, whereas there is conflicting evidence as to whether elevated second-trimester cell-free DNA is associated with a subsequent spontaneous preterm birth clinical event., Objective: The objective of the study was to evaluate the association between first- and second-trimester cell-free DNA fetal fraction and preterm birth., Study Design: This was a retrospective cohort study of women with singleton pregnancies at increased risk for aneuploidy who had cell-free DNA testing at 10-20 weeks' gestation between October 2011 and May 2014. The cohort was subdivided by gestational age at the time of cell-free DNA testing (10-14 weeks or 14.1-20 weeks). The primary outcome was preterm birth less than 37 weeks' gestation, and the secondary outcomes were preterm birth at less than 34 weeks' gestation and spontaneous preterm birth at less than 37 and 34 weeks' gestation., Results: Among 1349 pregnancies meeting inclusion criteria 119 (8.8 %) had a preterm birth prior to 37 weeks with 49 cases (3.6 %) delivering prior to 34 weeks. Whereas there was no significant association between fetal fraction and the preterm birth outcomes for those who underwent cell-free DNA testing at 10-14 weeks' gestation, there were significant associations among those screened at 14.1-20.0 weeks' gestation. Fetal fraction greater than or equal to the 95th percentile at 14.1-20.0 weeks' gestation was associated with an increased risk for preterm birth less than 37 and 34 weeks' gestation (adjusted odds ratio, 4.59; 95% confidence interval, 1.39-15.2; adjusted odds ratio, 22.0; 95% confidence interval, 5.02-96.9)., Conclusion: Elevated fetal fraction levels at 14.1-20.0 weeks' gestation were significantly associated with an increased incidence of preterm birth. Our findings warrant future exploration including validation in a larger, general population and investigation of the potential mechanisms that may be responsible for the initiation of preterm labor associated with increased fetal cell-free DNA., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: In 2006, the Alberta Ministry of Health issued a policy to implement fetal fibronectin (fFN) testing as a publicly funded service for pregnant women. The goals were to reduce maternity health care utilization and unnecessary treatment, which would result in cost-savings for the health system by more accurately diagnosing false preterm labour. We conducted a post-policy implementation review to determine whether the policy implementation achieved its goals., Methods: We assessed the impacts of fFN testing on clinical decision-making for ambulance transfer, hospital admission, and length of hospital stay by comparing these variables between the tested and untested patients. This post-implementation analysis was conducted separately for inpatients and outpatients and for true and false preterm labour, using multilevel regressions with episodes or visits being nested within patients. We then assessed the impact of fFN testing on costs to the health system by using decision-tree models populated with actual data and results from the regressions., Results: The additional information, provided by fFN testing, influenced clinical decision-making. However, physicians placed a greater significance on positive test results than on negative results, which resulted in an inadvertent increase in health care utilization. After including the costs of fFN testing, the total cost to the system increased by $4.2 million (in 2014 Canadian dollars) between 2008 and 2013, with contributions of $700 000 for false labour and $3.5 million for true preterm labour., Conclusion: The policy to adopt fFN testing in Alberta did not achieve the intended aims of reducing unnecessary health care utilization to achieve cost-savings for the health system. There was an inherent tendency to err on the side of caution, and physicians were influenced more by positive test results., (Copyright © 2016 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Background: Fetal fibronectin (fFN) is used as a biomarker for preterm delivery. Currently, its use is discouraged if there has been vaginal manipulation in the previous 24 hours., Objective: Our objective is to determine if there are differences between fFN results before and after vaginal manipulation in the form of sterile vaginal exam or transvaginal ultrasound., Study Design: This was a prospective observational cohort study at a single center of women between 22-33 6/7 weeks at risk for preterm delivery due to: (1) a history of preterm delivery, short cervix, or multifetal gestation; or (2) symptoms of preterm labor. We excluded women with vaginal bleeding or infection, placenta previa, ruptured membranes, cervical dilation >3 cm, or any form of vaginal manipulation in the previous 24 hours. Specimen A was collected prior to planned vaginal exam or transvaginal ultrasound and specimen B was collected within 4 hours. The agreement between specimens A and B was assessed using descriptive statistics. Test characteristics of specimens A and B using the outcome of preterm delivery (<37 weeks) were calculated., Results: In all, 310 specimen pairs from 237 women were collected. Specimen A was positive in 37 (12%) instances and negative in 273 (88%) while specimen B was positive in 39 (13%) and negative in 271 (87%). There were discordant results in 26 specimen pairs. Of these, 14 (5%) negative specimen A results subsequently became positive for specimen B, and 12 (32%) positive specimen A results became negative for specimen B. Overall, there was a 92% agreement between specimens A and B (confidence interval, 88-94%). The specificity of specimens A and B for preterm birth was 90% vs 89%, respectively, with a negative predictive value of 87% for both. The false-negative rate was 12.8% for specimen A and 13.3% for specimen B., Conclusion: There is a moderately high degree of agreement between prevaginal and postvaginal manipulation fFN results. Their test characteristics for evaluating preterm birth are similar with strong specificity and negative predictive values, and their false-negative rates are not clinically different. Consideration should be made to the utilization of postvaginal manipulation fFN when a prevaginal manipulation specimen is not available., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Preterm birth is a major concern in modern obstetrics, and an important source of morbidity and mortality in newborns. Among twin pregnancies, especially, preterm birth is highly prevalent, and it accounts for almost 50% of the complications observed in this obstetrical population. In this article, we review the existing literature regarding the prediction and prevention of preterm birth in both symptomatic and asymptomatic twin pregnancies. In asymptomatic twin pregnancies, the best two predictive tests were cervical length (CL) measurement and cervicovaginal fetal fibronectin (fFN) testing. A single measurement of transvaginal CL at 20-24 weeks of gestation <20 mm or <25 mm is a good predictor of spontaneous preterm birth at <28, <32, and <34 weeks of gestation. A CL beyond 25 mm is associated with a 2% risk for birth before 28 weeks and with a 65% chance for a term pregnancy. Cervicovaginal fFN may be slightly less accurate than CL; however, it has a high negative predictive value in women presenting with threatened preterm labor, as <2% of these women will deliver within one week if the fFN is negative. In symptomatic twin pregnancies, no tests have proven accurate in predicting the risk of preterm birth. For the prevention of preterm birth in asymptomatic twins, regardless of CL, no treatment including bed rest, limitation of home activities, prophylactic tocolysis, progesterone, or cerclage has been shown to reduce the rate of preterm birth. Cervical pessaries might be of interest in cases where there is a short cervix (<25 mm and <38 mm, respectively) but these results need to confirmed in future trials., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Preterm birth is the main cause of neonatal morbidity and mortality. This review provides an overview of antepartum and intrapartum management of threatened preterm birth. The most effective method to identify women at high risk of delivering within seven days is the combination of cervical length and fetal fibronectin test. Antenatal corticosteroids administered for 48 h improve neonatal outcome. Although tocolysis has been shown to prolong pregnancy, there is no evidence that tocolytic therapy improves neonatal outcomes. Intrapartum administration of magnesium sulfate improves neurologic outcomes, such as cerebral palsy and gross motor function. In women with preterm premature rupture of membranes, prophylactic antibiotic treatment with erythromycin improves short-term neonatal outcomes, but proof of long-term benefit is lacking. In threatened preterm birth with intact membranes, prophylactic antibiotic treatment is thought to be harmful. Critical appraisal of the long-term benefits and harms of all these treatments questions their use., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: Premature birth is associated with a wide range of complications in later life, including structural and functional neurological abnormalities and altered pain sensitivity. We investigated whether during anaesthesia premature-born children display different patterns of background EEG activity and exhibit increased responses to nociceptive stimuli., Methods: We examined background EEG and time-locked responses to clinical cannulation in 45 children (mean age (±SD) at study: 4.9(±3.0)years) under sevoflurane monoanaesthesia maintained at a steady-state end-tidal concentration of 2.5%. 15 were born prematurely (mean gestational age at birth: 29.2 ± 3.9 weeks) and 30 were age-matched term-born children., Results: Background levels of alpha and beta power were significantly lower in the premature-born children compared to term-born controls (p=0.048). Clinical cannulation evoked a significant increase in delta activity (p=0.032), which was not significantly different between the two groups (p=0.44)., Conclusions: The results indicate that whilst under anaesthesia premature-born children display different patterns of background brain activity compared to term-born children., Significance: As electrophysiological techniques are increasingly used by anaesthetists to gauge anaesthetic depth, differences in background levels of electrophysiological brain activity between premature and term-born children may be relevant when considering titration of anaesthetic dose., (Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: To assess the accuracy of the cervical phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) test to predict preterm birth in women with and without symptoms of preterm labor through the use of formal methods for systematic reviews and metaanalytic techniques., Data Sources: PubMed, Embase, Cinahl, Lilacs, and Medion (all from inception to June 30, 2015), reference lists, conference proceedings, and Google scholar., Study Eligibility Criteria: Cohort or cross-sectional studies that reported on the predictive accuracy of the cervical phIGFBP-1 test for preterm birth., Study Appraisal and Synthesis Methods: Two reviewers independently selected studies, assessed the risk of bias, and extracted the data. Summary receiver-operating characteristic curves, pooled sensitivities and specificities, and summary likelihood ratios were generated., Results: Forty-three studies met the inclusion criteria, of which 15 provided data on asymptomatic women (n = 6583) and 34 on women with an episode of preterm labor (n = 3620). Among asymptomatic women, the predictive accuracy of the cervical phIGFBP-1 test for preterm birth at <37, <34, and <32 weeks of gestation was minimal, with pooled sensitivities and specificities and summary positive and negative likelihood ratios ranging from 14% to 47%, 76% to 93%, 1.5 to 4.4, and 0.6 to 1.0, respectively. Among women with an episode of preterm labor, the test had a low predictive performance for delivery within 7 and 14 days of testing, and preterm birth at <34 and <37 weeks of gestation with pooled sensitivities and specificities and summary positive and negative likelihood ratios that varied between 60% and 68%, 77% and 81%, 2.7 and 3.5, and 0.4 and 0.5, respectively. A negative test result in women with an episode of preterm labor had a low to moderate accuracy to identify women who are not at risk for delivering within the next 48 hours (summary negative likelihood ratio of 0.28 in all women and 0.23 in women with singleton gestations)., Conclusion: Cervical phIGFBP-1 has the potential utility to identify patients with an episode of preterm labor who will not deliver within 48 hours. However, its overall predictive ability for the identification of symptomatic and asymptomatic women at risk for preterm birth is limited., (Published by Elsevier Inc.)

Objective: To determine the accuracy of changes in transvaginal sonographic cervical length over time in predicting preterm birth in women with singleton and twin gestations., Data Sources: PubMed, Embase, Cinahl, Lilacs, and Medion (all from inception to June 30, 2015), bibliographies, Google scholar, and conference proceedings. Cohort or cross-sectional studies reporting on the predictive accuracy for preterm birth of changes in cervical length over time., Study Appraisal and Synthesis Methods: Two reviewers independently selected studies, assessed the risk of bias, and extracted the data. Summary receiver-operating characteristic curves, pooled sensitivities and specificities, and summary likelihood ratios were generated., Results: Fourteen studies met the inclusion criteria, of which 7 provided data on singleton gestations (3374 women) and 8 on twin gestations (1024 women). Among women with singleton gestations, the shortening of cervical length over time had a low predictive accuracy for preterm birth at <37 and <35 weeks of gestation with pooled sensitivities and specificities, and summary positive and negative likelihood ratios ranging from 49% to 74%, 44% to 85%, 1.3 to 4.1, and 0.3 to 0.7, respectively. In women with twin gestations, the shortening of cervical length over time had a low to moderate predictive accuracy for preterm birth at <34, <32, <30, and <28 weeks of gestation with pooled sensitivities and specificities, and summary positive and negative likelihood ratios ranging from 47% to 73%, 84% to 89%, 3.8 to 5.3, and 0.3 to 0.6, respectively. There were no statistically significant differences between the predictive accuracies for preterm birth of cervical length shortening over time and the single initial and/or final cervical length measurement in 8 of 11 studies that provided data for making these comparisons. In the largest and highest-quality study, a single measurement of cervical length obtained at 24 or 28 weeks of gestation was significantly more predictive of preterm birth than any decrease in cervical length between these gestational ages., Conclusions: Change in transvaginal sonographic cervical length over time is not a clinically useful test to predict preterm birth in women with singleton or twin gestations. A single cervical length measurement obtained between 18 and 24 weeks of gestation appears to be a better test to predict preterm birth than changes in cervical length over time., (Published by Elsevier Inc.)

Objective of the Review: To identify predictors of preterm delivery in the context of threatened preterm labour., Main Points: Tobacco use and previous history of preterm delivery are the main anamnestic elements to predict preterm birth. High positive predictive value of vaginal examination is restricted to cases with strong cervical alterations like dilatation over 4 cm. In case of discrete cervical alterations, literature confirms the great interest for cervical length ultrasonographic measurement as it reduces false positive cases. Absence of fetal respiratory movements appears to be as sensitive as cervical length and could be more specific but its clinical use remains rare. Vaginal detection of fetal fibronectin is the most useful biomarker with high negative predictive value (>90%). Fibronectin quantitative test seems to enhance the positive predictive value. No other biomarker is currently used in clinical practice. Electromyography and elastography of the cervix appear to be promising approaches., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)