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Manual and intelligent navigation (i.e. fetal intelligent navigation echocardiography or FINE) by the operator are two methods to obtain standard fetal cardiac views from spatiotemporal image correlation (STIC) volumes. The objective was to compare the performance between manual and intelligent navigation (FINE) of the fetal heart by non-expert sonologists. In this prospective observational study, ten sonologists underwent formal training on both navigational methods. Subsequently, they were tested on their ability to obtain nine cardiac views from five STIC volumes of normal fetal hearts (19–28 gestational weeks) using such methods. The following parameters were determined for both methods: (1) success rate of obtaining nine cardiac views; (2) mean time to obtain nine cardiac views per sonologist; and (3) maximum number of cardiac views successfully obtained for each STIC volume. All fetal cardiac images obtained from 100 STIC volumes (50 for each navigational method) were reviewed by an expert in fetal echocardiography. Compared to manual navigation, FINE was associated with a significantly: (1) higher success rate of obtaining eight (excluding the abdomen view) appropriate cardiac views (92–100% vs. 56–88%; all p<0.05); (2) shorter mean time (minute:seconds) to obtain nine cardiac views (2:11 ± 0:37 vs. 15:49 ± 7:44; p<0.0001); and (3) higher success rate of obtaining all nine cardiac views for a given STIC volume (86 vs. 14%; p<0.001). When performed by non-expert sonologists, intelligent navigation (FINE) had a superior performance compared to manual navigation of the normal fetal heart. Specifically, FINE obtained appropriate fetal cardiac views in 92–100% of cases. [ABSTRACT FROM AUTHOR]

Cervical insufficiency generally refers to a condition in which there is mid-trimester cervical dilatation or protruding chorioamniotic membranes in the absence of uterine contractions. Such condition is a risk factor for spontaneous mid-trimester abortion or early preterm birth, and is associated with adverse neonatal outcomes. Both intra-amniotic infection and inflammation ascertained by amniocentesis have been identified in patients with cervical insufficiency, and are poor prognostic factors. A subset of patients with intra-amniotic inflammation will have no demonstrable microorganisms detected via cultivation or molecular methods, and therefore represent cases of sterile intra-amniotic inflammation. Amniotic fluid sludge (free-floating hyperechogenic material within the amniotic fluid in close proximity to the uterine cervix) identified on sonography is a biomarker for intra-amniotic infection and inflammation. Recent evidence suggests that intra-amniotic infection, as well as sterile intra-amniotic inflammation can be treated successfully using antimicrobial agents. We report a unique case in which administration of antibiotics in the presence of mid-trimester cervical insufficiency, sterile intra-amniotic inflammation, and amniotic fluid sludge was associated with resolution of the cervical findings, as demonstrated on both sonographic and speculum examination. The patient successfully underwent elective cesarean delivery at 36-2/7 weeks of gestation. This case illustrates that antibiotic therapy may be effective despite the presence of several high-risk pregnancy conditions, and that successful outcome is possible. [ABSTRACT FROM AUTHOR]

Ultrasound is an imaging modality that is highly operator dependent. This article reviews the challenges in learning how to perform obstetric sonography, as well as the processes necessary to acquire expert performance skills in sonography. Simulation-based education and learning, and the value of medical simulation are also discussed. Ultrasound simulators are an effective means of teaching obstetric sonography, because it provides training, deliberate practice, and performance evaluation/feedback which allows continuous and critical self-evaluation. We review evidence that simulation can improve performance in obstetric ultrasound examination, review current simulators, and discuss the current problems/gaps in ultrasound simulation. Optical positioning ultrasound simulation is a novel high-fidelity simulation learning system, which addresses many of these problems/gaps and is introduced for the first time here. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) is the leading organ-specific birth defect, as well as the leading cause of infant morbidity and mortality from congenital malformations. Therefore, a comprehensive screening examination of the fetal heart should be performed in all women to maximize the detection of CHD. Four-dimensional sonography with spatiotemporal image correlation (STIC) technology displays a cine loop of a complete single cardiac cycle in motion. A novel method known as Fetal Intelligent Navigation Echocardiography (or FINE) was previously developed to interrogate STIC volume datasets using "intelligent navigation" technology. Such method allows the automatic display of nine standard fetal echocardiography views required to diagnose most cardiac defects. FINE considerably simplifies fetal cardiac examinations and reduces operator dependency. It has both high sensitivity and specificity for the detection of CHD. Indeed, FINE has been integrated into several commercially available ultrasound platforms. Recently, eight novel and advanced features have been developed for the FINE method and they will be described herein. Such features can be categorized based upon their broad goals. The first goal is to simplify FINE further, and consists of the following features: (1) Auto fetal positioning (or FINE align); (2) Skip points; (3) Predictive cursor; (4) Static mode volume; and (5) Breech sweep. The second goal is to allow quantitative measurements to be performed on the cardiac views generated by FINE: (6) Automatic cardiac axis; and (7) Cardiac biometry. Finally, the last goal is to improve the success of obtaining fetal echocardiography view(s); and consists of (8) Maestro planar navigation. [ABSTRACT FROM AUTHOR]

Tetralogy of Fallot with pulmonary atresia, a severe form of tetralogy of Fallot, is characterized by the absence of flow from the right ventricle to the pulmonary arteries. This cardiac abnormality is challenging and complex due to its many different anatomic variants. The main source of variability is the pulmonary artery anatomy, ranging from well-formed, confluent pulmonary artery branches to completely absent native pulmonary arteries replaced by major aorto-pulmonary collateral arteries (MAPCAs) that provide all of the pulmonary blood flow. Since the four-chamber view is usually normal on prenatal sonography, the diagnosis may be missed unless additional cardiac views are studied. Fetal Intelligent Navigation Echocardiography (FINE) is a novel method developed recently that allows automatic generation of nine standard fetal echocardiography views in normal hearts by applying "intelligent navigation" technology to spatiotemporal image correlation volume datasets. We report herein for the first time, two different cases of tetralogy of Fallot with pulmonary atresia having variable sources of pulmonary blood flow in which the prenatal diagnosis was made successfully using the FINE method. Virtual Intelligent Sonographer Assistance (VIS-Assistance®) and automatic labeling (both features of FINE) were very helpful in making such diagnosis. [ABSTRACT FROM AUTHOR]

Fetal dextrocardia is a type of cardiac malposition where the major axis from base to apex points to the right side. This condition is usually associated with a wide spectrum of complex cardiac defects. As a result, dextrocardia is conceptually difficult to understand and diagnose on prenatal ultrasound. The advantage of four-dimensional sonography with spatiotemporal image correlation (STIC) is that this modality can facilitate fetal cardiac examination. A novel method known as fetal intelligent navigation echocardiography (FINE) allows automatic generation of nine standard fetal echocardiography views in normal hearts by applying intelligent navigation technology to STIC volume datasets. In fetuses with congenital heart disease, FINE is also able to demonstrate abnormal cardiac anatomy and relationships when there is normal cardiac axis and position. However, this technology has never been applied to cases of cardiac malposition. We report herein for the first time, a case of fetal dextrocardia and situs solitus with complex congenital heart disease in which the FINE method was invaluable in diagnosing multiple abnormalities and defining complex anatomic relationships. We also review the literature on prenatal sonographic diagnosis of dextrocardia (with an emphasis on situs solitus), as well as tricuspid atresia with its associated cardiac features. [ABSTRACT FROM AUTHOR]

'Manual navigation' by the operator is the standard method used to obtain information from two-dimensional and volumetric sonography. Two-dimensional sonography is highly operator dependent and requires extensive training and expertise to assess fetal anatomy properly. Most of the sonographic examination time is devoted to acquisition of images, while 'retrieval' and display of diagnostic planes occurs rapidly (essentially instantaneously). In contrast, volumetric sonography has a rapid acquisition phase, but the retrieval and display of relevant diagnostic planes is often time-consuming, tedious and challenging. We propose the term 'intelligent navigation' to refer to a new method of interrogation of a volume dataset whereby identification and selection of key anatomical landmarks allow the system to: 1) generate a geometrical reconstruction of the organ of interest; and 2) automatically navigate, find, extract and display specific diagnostic planes. This is accomplished using operator-independent algorithms that are both predictable and adaptive. Virtual Intelligent Sonographer Assistance (VIS-Assistance®) is a tool that allows operator-independent sonographic navigation and exploration of the surrounding structures in previously identified diagnostic planes. The advantage of intelligent (over manual) navigation in volumetric sonography is the short time required for both acquisition and retrieval and display of diagnostic planes. Intelligent navigation technology automatically realigns the volume, and reorients and standardizes the anatomical position, so that the fetus and the diagnostic planes are consistently displayed in the same manner each time, regardless of the fetal position or the initial orientation. Automatic labeling of anatomical structures, subject orientation and each of the diagnostic planes is also possible. Intelligent navigation technology can operate on conventional computers, and is not dependent on specific ultrasound platforms or on the use of software to perform manual navigation of volume datasets. Diagnostic planes and VIS-Assistance videoclips can be transmitted by telemedicine so that expert consultants can evaluate the images to provide an opinion. The end result is a user-friendly, simple, fast and consistent method of obtaining sonographic images with decreased operator dependency. Intelligent navigation is one approach to improve obstetrical sonography. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Objective: To describe a novel method (Fetal Intelligent Navigation Echocardiography (FINE)) for visualization of standard fetal echocardiography views from volume datasets obtained with spatiotemporal image correlation (STIC) and application of 'intelligent navigation' technology.Methods: We developed a method to: 1) demonstrate nine cardiac diagnostic planes; and 2) spontaneously navigate the anatomy surrounding each of the nine cardiac diagnostic planes (Virtual Intelligent Sonographer Assistance (VIS-Assistance®)). The method consists of marking seven anatomical structures of the fetal heart. The following echocardiography views are then automatically generated: 1) four chamber; 2) five chamber; 3) left ventricular outflow tract; 4) short-axis view of great vessels/right ventricular outflow tract; 5) three vessels and trachea; 6) abdomen/stomach; 7) ductal arch; 8) aortic arch; and 9) superior and inferior vena cava. The FINE method was tested in a separate set of 50 STIC volumes of normal hearts (18.6-37.2 weeks of gestation), and visualization rates for fetal echocardiography views using diagnostic planes and/or VIS-Assistance® were calculated. To examine the feasibility of identifying abnormal cardiac anatomy, we tested the method in four cases with proven congenital heart defects (coarctation of aorta, tetralogy of Fallot, transposition of great vessels and pulmonary atresia with intact ventricular septum).Results: In normal cases, the FINE method was able to generate nine fetal echocardiography views using: 1) diagnostic planes in 78-100% of cases; 2) VIS-Assistance® in 98-100% of cases; and 3) a combination of diagnostic planes and/or VIS-Assistance® in 98-100% of cases. In all four abnormal cases, the FINE method demonstrated evidence of abnormal fetal cardiac anatomy.Conclusions: The FINE method can be used to visualize nine standard fetal echocardiography views in normal hearts by applying 'intelligent navigation' technology to STIC volume datasets. This method can simplify examination of the fetal heart and reduce operator dependency. The observation of abnormal echocardiography views in the diagnostic planes and/or VIS-Assistance® should raise the index of suspicion for congenital heart disease. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective To describe a novel method (Fetal Intelligent Navigation Echocardiography ( FINE)) for visualization of standard fetal echocardiography views from volume datasets obtained with spatiotemporal image correlation ( STIC) and application of 'intelligent navigation' technology. Methods We developed a method to: 1) demonstrate nine cardiac diagnostic planes; and 2) spontaneously navigate the anatomy surrounding each of the nine cardiac diagnostic planes (Virtual Intelligent Sonographer Assistance ( VIS-Assistance®)). The method consists of marking seven anatomical structures of the fetal heart. The following echocardiography views are then automatically generated: 1) four chamber; 2) five chamber; 3) left ventricular outflow tract; 4) short-axis view of great vessels/right ventricular outflow tract; 5) three vessels and trachea; 6) abdomen/stomach; 7) ductal arch; 8) aortic arch; and 9) superior and inferior vena cava. The FINE method was tested in a separate set of 50 STIC volumes of normal hearts (18.6-37.2 weeks of gestation), and visualization rates for fetal echocardiography views using diagnostic planes and/or VIS-Assistance® were calculated. To examine the feasibility of identifying abnormal cardiac anatomy, we tested the method in four cases with proven congenital heart defects (coarctation of aorta, tetralogy of Fallot, transposition of great vessels and pulmonary atresia with intact ventricular septum). Results In normal cases, the FINE method was able to generate nine fetal echocardiography views using: 1) diagnostic planes in 78-100% of cases; 2) VIS-Assistance® in 98-100% of cases; and 3) a combination of diagnostic planes and/or VIS-Assistance® in 98-100% of cases. In all four abnormal cases, the FINE method demonstrated evidence of abnormal fetal cardiac anatomy. Conclusions The FINE method can be used to visualize nine standard fetal echocardiography views in normal hearts by applying 'intelligent navigation' technology to STIC volume datasets. This method can simplify examination of the fetal heart and reduce operator dependency. The observation of abnormal echocardiography views in the diagnostic planes and/or VIS-Assistance® should raise the index of suspicion for congenital heart disease. Published 2013. This article is a U.S. Government work and is in the public domain in the USA [ABSTRACT FROM AUTHOR]

Preterm birth is the leading cause of perinatal morbidity and mortality worldwide, and is the most important challenge to modern obstetrics. A major obstacle has been that preterm birth is treated (implicitly or explicitly) as a single condition. Two thirds of preterm births occur after the spontaneous onset of labor, and the remaining one third after 'indicated' preterm birth; however, the causes of spontaneous preterm labor and 'indicated' preterm birth are different. Spontaneous preterm birth is a syndrome caused by multiple etiologies, one of which is a decline in progesterone action, which induces cervical ripening. A sonographic short cervix (identified in the midtrimester) is a powerful predictor of spontaneous preterm delivery. Randomized clinical trials and individual patient meta-analyses have shown that vaginal progesterone reduces the rate of preterm delivery at <33 weeks of gestation by 44%, along with the rate of admission to the neonatal intensive care unit, respiratory distress syndrome, requirement for mechanical ventilation, and composite neonatal morbidity/mortality score. There is no evidence that 17-α-hydroxyprogesterone caproate can reduce the rate of preterm delivery in women with a short cervix, and therefore, the compound of choice is natural progesterone (not the synthetic progestin). Routine assessment of the risk of preterm birth with cervical ultrasound coupled with vaginal progesterone for women with a short cervix is cost-effective, and the implementation of such a policy is urgently needed. Vaginal progesterone is as effective as cervical cerclage in reducing the rate of preterm delivery in women with a singleton gestation, history of preterm birth, and a short cervix (<25 mm). [ABSTRACT FROM AUTHOR]

In this article the author discusses the importance of ultrasound to improve the assessment of labor progress. It cites various studies that examine fetal head station diagnosis, translabial ultrasound, and progress in the second stage of labor. It also explores the role of three-dimensional sonography and ultrasound in obstetrics.

Objective The aim of the study is to explore the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on preterm birth at different gestational ages and fetal death in the state of Michigan. Study Design Data on live births and fetal deaths in the state of Michigan from March to November in the years 2017 through 2020 were obtained from Michigan Department of Health and Human Services (MDHHS). Preterm birth rate, fetal death rate (per 1,000 live births) overall and stratified by race and maternal comorbidities during the period of pandemic (March–November 2020) were compared with the same period (March–November) in the prepandemic years (2017–2019). Results Of 328,879 live births and 1,470 fetal deaths during the study period, 77,983 live births and 242 fetal deaths were reported in 2020. Compared with prepandemic years, fetal death rate per 1,000 live births was significantly lower in 2020 (3.1 vs. 4.7 [2017], 5.2 [2018], 4.4 [2019], p -value <0.001). The adjusted risk for fetal death in 2020 was decreased (odds ratio [OR] = 0.64 [95% confidence interval (CI): 0.56–0.74], p <0.0001), compared with prepandemic years. Fetal death was significantly associated with African-American race, pregnancy hypertension and prepregnancy diabetes. No significant difference in the proportion of preterm births (<37 weeks' gestation) was noted between pandemic and prepandemic years (9.9 vs. 10.0%, p = 0.50). There was no significant difference in the risk of preterm birth across gestational age strata (<28, 28–31 6/7 , 32–36 6/7 , 37–41 6/7 , and >42 weeks) between pandemic and prepandemic years on multinomial analysis. Significant associations with preterm birth across all years included African American race, lower level of maternal education, pregnancy-induced hypertension, chronic hypertension, prepregnancy diabetes, congenital anomalies, previous preterm birth, and prolonged rupture of membranes >12 hours. Conclusion Fetal death rate was significantly lower whereas preterm births remained unchanged during pandemic in comparison with prepandemic years in the state of Michigan. Key Points A decrease in fetal death rate was noted during SARS CoV-2 pandemic in the State of Michigan. Overall state-wide rates of preterm birth did not change in 2020, compared to previous years. Significant risk factors associated with preterm birth and fetal deaths did not differ between prepandemic and pandemic years. [ABSTRACT FROM AUTHOR]

Acute cervical insufficiency is frequently associated with subclinical intra-amniotic inflammation and intra-amniotic infection. Amniotic fluid analysis has been recommended prior to the placement of a cervical cerclage given that preexisting infection is associated with adverse pregnancy outcome. We report a case for which commonly available laboratory tests—amniotic fluid Gram stain, white blood cell count, and glucose concentration—did not detect either intra-amniotic inflammation, diagnosed by elevated amniotic fluid interleukin-6, or intra-amniotic infection, diagnosed by cultivation. Following cerclage placement, the patient developed clinical chorioamnionitis and bacteremia and experienced a spontaneous mid-trimester pregnancy loss. This case illustrates the need for a rapid and sensitive point-of-care test capable of detecting infection or inflammation, given recent evidence in support of treatment of intra-amniotic infection and intra-amniotic inflammation with antimicrobial agents. [ABSTRACT FROM AUTHOR]

Nonovert disseminated intravascular coagulation (DIC) is a subclinical hemostatic dysfunction that has not yet reached the decompensation stage. The detection of pregnant patients at this stage may assist in the identification of those who will develop severe obstetrical hemorrhage, as it is one of the leading causes for preventable maternal mortality. Currently, nonovert DIC is diagnosed by a scoring system based on nonpregnant patients, originally generated by the International Society on Thrombosis and Hemostasis (ISTH), which does not address the physiologic changes of the hemostatic system during pregnancy. (1) To develop a pregnancy-specific nonovert DIC score, (2) to determine the diagnostic performance of this score in detecting women at risk for obstetrical hemorrhage requiring blood product transfusion, and (3) to compare it to the existing ISTH nonovert DIC score. This retrospective study has longitudinal and cross-sectional components and includes three steps: (1) characterization of the longitudinal changes in the components of modified ISTH nonovert DIC scores, including these parameters – fibrinogen, antithrombin III, protein C, prothrombin time (PT), platelets, thrombin-antithrombin (TAT) complex, and D-dimer – during gestation in a group of normal pregnancies (n = 50); (2) development of a pregnancy-specific nonovert DIC score in a cross-sectional design of high-risk (n = 152) and control (n = 50) pregnancies, based on the predictive performance of each analyte for the detection of women at risk for obstetrical hemorrhage requiring blood product transfusion and a logistic regression model; and (3) comparison between the diagnostic performance of the pregnancy-specific nonovert DIC score and the modified ISTH nonovert DIC score to detect, upon admission, women who are at increased risk for subsequent development of obstetrical hemorrhage requiring blood product transfusion. (1) The study cohort included 202 patients, of which 21 (10%) had obstetrical hemorrhage that required blood product transfusion and were considered to have nonovert DIC; (2) using the nonpregnant ISTH nonovert DIC score, 92% of the patients had a D-dimer concentration above the 0.5 mg/L threshold, and only 2% were identified to have a low fibrinogen concentration (<100 mg/dL); thus, this scoring system was unable to identify any of the patients with nonovert DIC based on the suggested cutoff of a score of ≥5; (3) the parameters included in the pregnancy-specific nonovert DIC score were selected based on their contribution to the performance of the model for the prediction of women at risk for obstetrical hemorrhage requiring blood product transfusion; as a result, we excluded the PT difference parameter from the score and the TAT complex concentration was added; and (4) a pregnancy-specific nonovert DIC score of ≥3 had a sensitivity of 71.4% and a specificity of 77.9% to identify patients at risk for obstetrical hemorrhage requiring blood product transfusion. We propose (1) a pregnancy-specific nonovert DIC score adjusted for the physiologic changes in the hemostatic system during gestation; and (2) that the pregnancy-specific nonovert DIC score can be a useful tool for the identification of patients at risk for obstetrical hemorrhage requiring blood product transfusion. [ABSTRACT FROM AUTHOR]

Intra-amniotic infection, defined by the presence of microorganisms in the amniotic cavity, is often accompanied by intra-amniotic inflammation. Occasionally, laboratories report the growth of bacteria or the presence of microbial nucleic acids in amniotic fluid in the absence of intra-amniotic inflammation. This study was conducted to determine the clinical significance of the presence of bacteria in amniotic fluid samples in the absence of intra-amniotic inflammation. A retrospective cross-sectional study included 360 patients with preterm labor and intact membranes who underwent transabdominal amniocentesis for evaluation of the microbial state of the amniotic cavity as well as intra-amniotic inflammation. Cultivation techniques were used to isolate microorganisms, and broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) was utilized to detect the nucleic acids of bacteria, viruses, and fungi. Patients whose amniotic fluid samples evinced microorganisms but did not indicate inflammation had a similar perinatal outcome to those without microorganisms or inflammation [amniocentesis-to-delivery interval (p=0.31), spontaneous preterm birth before 34 weeks (p=0.83), acute placental inflammatory lesions (p=1), and composite neonatal morbidity (p=0.8)]. The isolation of microorganisms from a sample of amniotic fluid in the absence of intra-amniotic inflammation is indicative of a benign condition, which most likely represents contamination of the specimen during the collection procedure or laboratory processing rather than early colonization or infection. [ABSTRACT FROM AUTHOR]

: ObjectiveTo estimate the usefulness of absent nasal bone by ultrasound in the prenatal detection of second-trimester fetuses with trisomy 21.: MethodsThis was a matched case–control study of sonograms from January 1, 1997 to April 30, 2002. Genetic sonograms and facial profile pictures of all fetuses that were subsequently proven to have trisomy 21 were reviewed (study group). A control group was identified during the same study period by using a 4-to-1 ratio matching for gestational age at the time of the ultrasound examination. The sensitivity and specificity of absent fetal nasal bone for trisomy 21 were determined, and overlap with other ultrasound aneuploidy markers was assessed.: ResultsForty fetuses were identified with trisomy 21; in 29 (72.5%) a facial profile had been obtained. Of the 160 controls, 102 (64%) had facial profiles documented. Of the 29 fetuses with trisomy 21 with facial profile available, 12 had absent nasal bone (sensitivity 41%). None of the 102 control fetuses with facial profiles available had absent nasal bone (specificity 100%). The sensitivity of genetic ultrasound was increased from 83% (24 of 29) to 90% (26 of 29) by adding absent nasal bone to the other ultrasound aneuploidy markers.: ConclusionIn the second trimester of pregnancy, absent nasal bone has a sensitivity of 41% and a specificity of 100% in detecting fetal trisomy 21. Absent fetal nasal bone may be added to the list of ultrasound aneuploidy markers evaluated during a genetic sonogram. [Copyright &y& Elsevier]

The amniotic fluid (AF) cell-free RNA was shown to reflect physiological and pathological processes in pregnancy, but its value in the prediction of spontaneous preterm delivery is unknown. Herein we profiled cell-free RNA in AF samples collected from women who underwent transabdominal amniocentesis after an episode of spontaneous preterm labor and subsequently delivered within 24 h (n = 10) or later (n = 28) in gestation. Expression of known placental single-cell RNA-Seq signatures was quantified in AF cell-free RNA and compared between the groups. Random forest models were applied to predict time-to-delivery after amniocentesis. There were 2385 genes differentially expressed in AF samples of women who delivered within 24 h of amniocentesis compared to gestational age-matched samples from women who delivered after 24 h of amniocentesis. Genes with cell-free RNA changes were associated with immune and inflammatory processes related to the onset of labor, and the expression of placental single-cell RNA-Seq signatures of immune cells was increased with imminent delivery. AF transcriptomic prediction models captured these effects and predicted delivery within 24 h of amniocentesis (AUROC = 0.81). These results may inform the development of biomarkers for spontaneous preterm birth. [ABSTRACT FROM AUTHOR]

Spontaneous preterm labor is an obstetrical syndrome accounting for approximately 65–70% of preterm births, the latter being the most frequent cause of neonatal death and the second most frequent cause of death in children less than five years of age worldwide. The purpose of this study was to determine and compare to uncomplicated pregnancies (1) the frequency of placental disorders of villous maturation in spontaneous preterm labor; (2) the frequency of other placental morphologic characteristics associated with the preterm labor syndrome; and (3) the distribution of these lesions according to gestational age at delivery and their severity. A case-control study of singleton pregnant women was conducted that included (1) uncomplicated pregnancies (controls, n=944) and (2) pregnancies with spontaneous preterm labor (cases, n=438). All placentas underwent histopathologic examination. Patients with chronic maternal diseases (e.g., chronic hypertension, diabetes mellitus, renal disease, thyroid disease, asthma, autoimmune disease, and coagulopathies), fetal malformations, chromosomal abnormalities, multifetal gestation, preeclampsia, eclampsia, preterm prelabor rupture of the fetal membranes, gestational hypertension, gestational diabetes mellitus, and HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome were excluded from the study. Compared to the controls, the most prevalent placental lesions among the cases were the disorders of villous maturation (31.8% [106/333] including delayed villous maturation 18.6% [62/333] vs. 1.4% [6/442], q<0.0001, prevalence ratio 13.7; and accelerated villous maturation 13.2% [44/333] vs. 0% [0/442], q<0.001). Other lesions in decreasing order of prevalence included hypercapillarized villi (15.6% [68/435] vs. 3.5% [33/938], q<0.001, prevalence ratio 4.4); nucleated red blood cells (1.1% [5/437] vs. 0% [0/938], q<0.01); chronic inflammatory lesions (47.9% [210/438] vs. 29.9% [282/944], q<0.0001, prevalence ratio 1.6); fetal inflammatory response (30.1% [132/438] vs. 23.2% [219/944], q<0.05, prevalence ratio 1.3); maternal inflammatory response (45.5% [195/438] vs. 36.1% [341/944], q<0.01, prevalence ratio 1.2); and maternal vascular malperfusion (44.5% [195/438] vs. 35.7% [337/944], q<0.01, prevalence ratio 1.2). Accelerated villous maturation did not show gestational age-dependent association with any other placental lesion while delayed villous maturation showed a gestational age-dependent association with acute placental inflammation (q-value=0.005). Disorders of villous maturation are present in nearly one-third of the cases of spontaneous preterm labor. [ABSTRACT FROM AUTHOR]

Clinical chorioamnionitis at term is considered the most common infection-related diagnosis in labor and delivery units worldwide. The syndrome affects 5–12% of all term pregnancies and is a leading cause of maternal morbidity and mortality as well as neonatal death and sepsis. The objectives of this study were to determine the (1) amniotic fluid microbiology using cultivation and molecular microbiologic techniques; (2) diagnostic accuracy of the clinical criteria used to identify patients with intra-amniotic infection; (3) relationship between acute inflammatory lesions of the placenta (maternal and fetal inflammatory responses) and amniotic fluid microbiology and inflammatory markers; and (4) frequency of neonatal bacteremia. This retrospective cross-sectional study included 43 women with the diagnosis of clinical chorioamnionitis at term. The presence of microorganisms in the amniotic cavity was determined through the analysis of amniotic fluid samples by cultivation for aerobes, anaerobes, and genital mycoplasmas. A broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry was also used to detect bacteria, select viruses, and fungi. Intra-amniotic inflammation was defined as an elevated amniotic fluid interleukin-6 (IL-6) concentration ≥2.6 ng/mL. (1) Intra-amniotic infection (defined as the combination of microorganisms detected in amniotic fluid and an elevated IL-6 concentration) was present in 63% (27/43) of cases; (2) the most common microorganisms found in the amniotic fluid samples were Ureaplasma species, followed by Gardnerella vaginalis; (3) sterile intra-amniotic inflammation (elevated IL-6 in amniotic fluid but without detectable microorganisms) was present in 5% (2/43) of cases; (4) 26% of patients with the diagnosis of clinical chorioamnionitis had no evidence of intra-amniotic infection or intra-amniotic inflammation; (5) intra-amniotic infection was more common when the membranes were ruptured than when they were intact (78% [21/27] vs. 38% [6/16]; p=0.01); (6) the traditional criteria for the diagnosis of clinical chorioamnionitis had poor diagnostic performance in identifying proven intra-amniotic infection (overall accuracy, 40–58%); (7) neonatal bacteremia was diagnosed in 4.9% (2/41) of cases; and (8) a fetal inflammatory response defined as the presence of severe acute funisitis was observed in 33% (9/27) of cases. Clinical chorioamnionitis at term, a syndrome that can result from intra-amniotic infection, was diagnosed in approximately 63% of cases and sterile intra-amniotic inflammation in 5% of cases. However, a substantial number of patients had no evidence of intra-amniotic infection or intra-amniotic inflammation. Evidence of the fetal inflammatory response syndrome was frequently present, but microorganisms were detected in only 4.9% of cases based on cultures of aerobic and anaerobic bacteria in neonatal blood. [ABSTRACT FROM AUTHOR]

Objective: The aims of this study were to ascertain the frequency of disorders of villous maturation in fetal death and to also delineate other placental histopathologic lesions in fetal death. Methods: This was a retrospective observational cohort study of fetal deaths occurring among women between January 2004 and January 2016 at Hutzel Women's Hospital, Detroit, MI, USA. Cases comprised fetuses with death beyond 20 weeks' gestation. Fetal deaths with congenital anomalies and multiple gestations were excluded. Controls included pregnant women without medical/obstetrical complications and delivered singleton, term (37–42 weeks) neonate with 5-min Apgar score ≥7 and birthweight between the 10th and 90th percentiles. Results: Ninety-two percent (132/143) of placentas with fetal death showed placental histologic lesions. Fetal deaths were associated with (1) higher frequency of disorders of villous maturation [44.0% (64/143) vs. 1.0% (4/405), P < 0.0001, prevalence ratio, 44.6; delayed villous maturation, 22% (31/143); accelerated villous maturation, 20% (28/143); and maturation arrest, 4% (5/143)]; (2) higher frequency of maternal vascular malperfusion lesions [75.5% (108/143) vs. 35.7% (337/944), P < 0.0001, prevalence ratio, 2.1] and fetal vascular malperfusion lesions [88.1% (126/143) vs. 19.7% (186/944), P < 0.0001, prevalence ratio, 4.5]; (3) higher frequency of placental histologic patterns suggestive of hypoxia [59.0% (85/143) vs. 9.3% (82/942), P < 0.0001, prevalence ratio, 6.8]; and (4) higher frequency of chronic inflammatory lesions [53.1% (76/143) vs. 29.9% (282/944), P < 0.001, prevalence ratio 1.8]. Conclusion: This study demonstrates that placentas of women with fetal death were 44 times more likely to present disorders of villous maturation compared to placentas of those with normal pregnancy. This suggests that the burden of placental disorders of villous maturation lesions is substantial. [ABSTRACT FROM AUTHOR]

Objective: To evaluate a dual-imaging modality approach to obtain a combined estimation of venous blood oxygenation (SνO2) using susceptibility-weighted magnetic resonance imaging (SWI-MRI), and blood perfusion using power Dopp-ler ultrasound (PDU) and fractional moving blood volume (FMBV) in the brain of normal growth and growth-restricted fetuses.Methods: Normal growth (n = 33) and growth-restricted fetuses (n = 10) from singleton pregnancies between 20 and 40 weeks of gestation were evaluated. MRI was performed and SνO2 was calculated using SWI-MRI data obtained in the straight section of the superior sagittal sinus. Blood perfusion was estimated using PDU and FMBV from the frontal lobe in a mid-sagittal plane of the fetal brain. The association between fetal brain SνO2 and FMBV, and the distribution of SνO2 and FMBV values across gestation were calculated for both groups.Results: In growth-restricted fetuses, the brain SνO2 values were similar, and the FMBV values were higher across gestation as compared to normal growth fetuses. There was a significantly positive association between SνO2 and FMBV values (slope = 0.38 ± 0.12; r = 0.7; p = 0.02) in growth-restricted fetuses. In normal growth fetuses, SνO2 showed a mild decreasing trend (slope = -0.7 ± 0.4; p = 0.1), whereas FMBV showed a mild increasing trend (slope = 0.2 ± 0.2; p = 0.2) with advancing gestation, and a mild but significant negative association (slope = -0.78 ± 0.3; r = -0.4; p = 0.04) between these two estimates.Conclusion: Combined MRI (SWI) and ultrasound (FMBV) techniques showed a significant association between cerebral blood oxygenation and blood perfusion in normal growth and growth-restricted fetuses. This dual-imaging approach could contribute to the early detection of fetal "brain sparing" and brain oxygen saturation changes in high-risk pregnancies. [ABSTRACT FROM AUTHOR]

Objective: ELABELA is a newly discovered peptide hormone that appears to be implicated in the mechanisms leading to preeclampsia, independently of angiogenic factors. The aim of the current study was to investigate whether women with early- or late-onset preeclampsia have altered ELABELA plasma concentrations compared to gestational-age-matched normal pregnant women.Methods: This retrospective cross-sectional study focused on the maternal plasma samples collected from 232 women with a singleton pregnancy who were allocated into the following groups: (1) early-onset preeclampsia (<34 weeks of gestation, N = 56); (2) late-onset preeclampsia (≥34 weeks of gestation, N = 57); and (3) gestational-age-matched controls with a normal pregnancy [(<34 weeks of gestation, N = 59); (≥34 weeks of gestation, N = 60)]. ELABELA plasma concentrations were determined using a validated enzyme immunoassay.Results: (1) ELABELA plasma concentrations are higher in patients with late-onset preeclampsia compared with those from gestational-age-matched controls with a normal pregnancy [median: 7.99 ng/mL (IQR, 5.3-13.95 ng/mL) versus median: 4.17 ng/mL (IQR, 3-11.19 ng/mL), p =.001]; (2) ELABELA plasma concentrations in patients with early-onset preeclampsia do not differ from those of normal pregnant women [median: 6.09 ng/mL (IQR, 2.8-10.66 ng/mL) versus median: 4.02 ng/mL (IQR, 3.26-7.49), p = .32]; and (3) ELABELA plasma concentrations are higher in patients with late-onset preeclampsia compared to those with early-onset preeclampsia [median: 7.99 ng/mL (IQR, 5.3-13.95 ng/mL) versus median: 6.09 ng/mL (IQR, 2.8-10.66 ng/mL), p = .01].Conclusion: ELABELA plasma concentrations are higher in patients with late-onset preeclampsia than in those with a normal pregnancy. However, women with early-onset preeclampsia have similar ELABELA plasma concentrations to those with a normal pregnancy. These findings provide insight into the ELABELA axis during the human syndrome of preeclampsia. In addition, these data support the concept that different pathophysiologic mechanisms are implicated in early- and late-onset preeclampsia. [ABSTRACT FROM AUTHOR]

Objective: Upon inflammasome activation, the adaptor protein of the inflammasome ASC (apoptosis-associated speck-like protein containing a CARD) forms intracellular specks, which can be released into the extracellular space. The objectives of this study were to investigate whether (1) extracellular ASC is present in the amniotic fluid of women who delivered at term; (2) amniotic fluid ASC concentrations are greater in women who underwent spontaneous labor at term than in those who delivered at term in the absence of labor; and (3) amniotic epithelial and mesenchymal cells can form intracellular ASC specks in vitro. Methods: This retrospective cross-sectional study included amniotic fluid samples from 41 women who delivered at term in the absence of labor (n = 24) or underwent spontaneous labor at term (n = 17). Amniotic epithelial and mesenchymal cells were also isolated from the chorioamniotic membranes obtained from a separate group of women who delivered at term (n = 3), in which ASC speck formation was assessed by confocal microscopy. Monocytes from healthy individuals were used as positive controls for ASC speck formation (n = 3). Results: (1) The adaptor protein of the inflammasome ASC is detectable in the amniotic fluid of women who delivered at term; (2) amniotic fluid ASC concentration was higher in women who underwent spontaneous labor at term than in those who delivered at term without labor; and (3) amniotic epithelial and mesenchymal cells are capable of forming ASC specks and/or filaments in vitro. Conclusion: Amniotic fluid ASC concentrations are increased in women who undergo spontaneous labor at term. Amniotic epithelial and mesenchymal cells are capable of forming ASC specks, suggesting that these cells are a source of extracellular ASC in the amniotic fluid. These findings provide in vivo evidence that there is inflammasome activation in the amniotic cavity during the physiological process of labor at term. [ABSTRACT FROM AUTHOR]

Objective: Upon inflammasome activation, the adaptor protein of the inflammasome ASC (apoptosis-associated speck-like protein containing a CARD) forms intracellular specks, which can be released into the extracellular space. The objectives of this study were to investigate whether (1) extracellular ASC is present in the amniotic fluid of women who delivered at term; (2) amniotic fluid ASC concentrations are greater in women who underwent spontaneous labor at term than in those who delivered at term in the absence of labor; and (3) amniotic epithelial and mesenchymal cells can form intracellular ASC specks in vitro.Methods: This retrospective cross-sectional study included amniotic fluid samples from 41 women who delivered at term in the absence of labor (n = 24) or underwent spontaneous labor at term (n = 17). Amniotic epithelial and mesenchymal cells were also isolated from the chorioamniotic membranes obtained from a separate group of women who delivered at term (n = 3), in which ASC speck formation was assessed by confocal microscopy. Monocytes from healthy individuals were used as positive controls for ASC speck formation (n = 3).Results: (1) The adaptor protein of the inflammasome ASC is detectable in the amniotic fluid of women who delivered at term; (2) amniotic fluid ASC concentration was higher in women who underwent spontaneous labor at term than in those who delivered at term without labor; and (3) amniotic epithelial and mesenchymal cells are capable of forming ASC specks and/or filaments in vitro.Conclusion: Amniotic fluid ASC concentrations are increased in women who undergo spontaneous labor at term. Amniotic epithelial and mesenchymal cells are capable of forming ASC specks, suggesting that these cells are a source of extracellular ASC in the amniotic fluid. These findings provide in vivo evidence that there is inflammasome activation in the amniotic cavity during the physiological process of labor at term. [ABSTRACT FROM AUTHOR]

Objectives: To present the feasibility of performing quantitative susceptibility mapping (QSM) in the human fetus to evaluate the oxygenation (SvO2) of cerebral venous blood in vivo.Methods: Susceptibility weighted imaging (SWI) data were acquired from healthy pregnant subjects (n = 21, median = 31.3 weeks, interquartile range = 8.8 weeks). The susceptibility maps were generated from the SWI-phase images using a modified QSM processing pipeline, optimised for fetal applications. The processing pipeline is as follows: (1) mild high-pass filtering followed by quadratic fitting of the phase images to eliminate background phase variations; (2) manual creation of a fetal brain mask that includes the superior sagittal sinus (SSS); (3) inverse filtering of the resultant masked phase images using a truncated k-space approach with geometric constraint. Further, the magnetic susceptibility, ∆χv and corresponding putative SvO2 of the SSS were quantified from the generated susceptibility maps. Systematic error in the measured SvO2 due to the modified pipeline was also studied through simulations.Results: Simulations showed that the systematic error in SvO2 when using a mask that includes a minimum of 5 voxels around the SSS and five slices remains < 3% for different orientations of the vessel relative to the main magnetic field. The average ∆χv in the SSS quantified across all gestations was 0.42 ± 0.03 ppm. Based on ∆χv, the average putative SvO2 in the SSS across all fetuses was 67% ± 7%, which is in good agreement with published studies.Conclusions: This in vivo study demonstrates the feasibility of using QSM in the human fetal brain to estimate ∆χv and SvO2.Key Points: • A modified quantitative susceptibility mapping (QSM) processing pipeline is tested and presented for the human fetus.• QSM is feasible in the human fetus for measuring magnetic susceptibility and oxygenation of venous blood in vivo.• Blood magnetic susceptibility values from MR susceptometry and QSM agree with each other in the human fetus. [ABSTRACT FROM AUTHOR]

Objectives: To investigate mechanisms of in utero death in normally formed fetuses by measuring amniotic fluid (AF) biomarkers for hypoxia (erythropoietin [EPO]), myocardial damage (cardiac troponin I [cTnI]) and brain injury (glial fibrillary acidic protein [GFAP]), correlated with risk factors for fetal death and placental histopathology. Methods: This retrospective, observational cohort study included intrauterine deaths with transabdominal amniocentesis prior to induction of labor. Women with a normal pregnancy and an indicated amniocentesis at term were randomly selected as controls. AF was assayed for EPO, cTnI and GFAP using commercial immunoassays. Placental histopathology was reviewed, and CD15-immunohistochemistry was used. Analyte concentrations >90th centile for controls were considered "raised". Raised AF EPO, AF cTnI and AF GFAP concentrations were considered evidence of hypoxia, myocardial and brain injury, respectively. Results: There were 60 cases and 60 controls. Hypoxia was present in 88% (53/60), myocardial damage in 70% (42/60) and brain injury in 45% (27/60) of fetal deaths. Hypoxic fetuses had evidence of myocardial injury, brain injury or both in 77% (41/53), 49% (26/53) and 13% (7/53) of cases, respectively. Histopathological evidence for placental dysfunction was found in 74% (43/58) of these cases. Conclusion: Hypoxia, secondary to placental dysfunction, was found to be the mechanism of death in the majority of fetal deaths among structurally normal fetuses. Ninety-one percent of hypoxic fetal deaths sustained brain, myocardial or both brain and myocardial injuries in utero. Hypoxic myocardial injury was an attributable mechanism of death in 70% of the cases. Non-hypoxic cases may be caused by cardiac arrhythmia secondary to a cardiac conduction defect. [ABSTRACT FROM AUTHOR]

Objective: To determine the frequency and type of histopathologic lesions in placentas delivered by women with a normal pregnancy outcome. Methods: This retrospective cohort study included placental samples from 944 women with a singleton gestation who delivered at term without obstetrical complications. Placental lesions were classified into the following four categories as defined by the Society for Pediatric Pathology and by our unit: (1) acute placental inflammation, (2) chronic placental inflammation, (3) maternal vascular malperfusion and (4) fetal vascular malperfusion. Results: (1) Seventy-eight percent of the placentas had lesions consistent with inflammatory or vascular lesions; (2) acute inflammatory lesions were the most prevalent, observed in 42.3% of the placentas, but only 1.0% of the lesions were severe; (3) acute inflammatory lesions were more common in the placentas of women with labor than in those without labor; (4) chronic inflammatory lesions of the placenta were present in 29.9%; and (5) maternal and fetal vascular lesions of malperfusion were detected in 35.7% and 19.7%, respectively. Two or more lesions with maternal or fetal vascular features consistent with malperfusion (high-burden lesions) were present in 7.4% and 0.7%, respectively. Conclusion: Most placentas had lesions consistent with inflammatory or vascular lesions, but severe and/or high-burden lesions were infrequent. Mild placental lesions may be interpreted either as acute changes associated with parturition or as representative of a subclinical pathological process (intra-amniotic infection or sterile intra-amniotic inflammation) that did not affect the clinical course of pregnancy. [ABSTRACT FROM AUTHOR]

Background: Normal development of the human placenta, referred to as villous tree maturation, entails formation of the vasculosyncytial membranes. These structures develop by the approximation of syncytiotrophoblasts with the villous capillary endothelium and constitute the most efficient sites of gaseous exchange in the placenta. Defective maturation of the villous tree can lead to deficient vasculosyncytial membranes, implicated in the high incidence of hypoxic complications. Hypoxia, in turn, can stimulate production of erythropoietin, whereby increased fetal plasma or amniotic fluid concentrations of this hormone reflect fetal hypoxemia. The current study was undertaken to determine whether delayed villous maturation is associated with changes in amniotic fluid erythropoietin concentrations. Methods: Placental histologic examination was performed using hematoxylin and eosin. Subsequent to histologic assessment of delayed villous maturation, the diagnosis was confirmed with CD-15 immunohistochemistry. The controls (n = 61) were pregnancies without villous maturation abnormalities, and cases (n = 5) were pregnancies with delayed villous maturation. Amniotic fluid erythropoietin concentrations were measured using a specific immunoassay. Results: Concentrations of erythropoietin in the amniotic fluid (1) of controls were less than the limit of detection and (2) of cases with delayed villous maturation were significantly higher than those of controls (P-value = 0.048). Conclusion: Delayed villous maturation is associated with higher concentrations of amniotic fluid erythropoietin. [ABSTRACT FROM AUTHOR]

Objective: We aimed to determine the differences in the pattern and magnitude of thrombin generation between patients with preeclampsia (PE) and those with a small-for-gestational-age (SGA) fetus.Methods: This cross-sectional study included women in the following groups: (1) normal pregnancy (NP) (n = 49); (2) PE (n = 56); and (3) SGA (n = 28). Maternal plasma thrombin generation (TGA) was measured, calculating: (a) lag time (LT); (b) velocity index (VI); (c) peak thrombin concentration (PTC); (d) time-to-peak thrombin concentration (TPTC); and (e) endogenous thrombin potential (ETP).Results: (1) The median TPTC, VI, and ETP differed among the groups (p = .001, p = .006, p < .0001); 2) the median ETP was higher in the PE than in the NP (p < .0001) and SGA (p = .02) groups; 3) patients with SGA had a shorter median TPTC and a higher median VI than the NP (p = .002, p = .012) and PE (p < .0001, p = .006) groups.Conclusions: (1) Patients with PE had higher in vivo thrombin generation than women with NP and those with an SGA fetus; (2) the difference in TGA patterns between PE and SGA suggests that the latter group had faster TGA, while patients with PE had a longer reaction, generating more thrombin. This observation is important for the identification of a subset of patients who might benefit from low molecular-weight heparin. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to determine whether the activity of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in the plasma of women with preeclampsia (PE) and small for gestational age (SGA) neonate differ from that of normal pregnant women and whether they are related to specific placental lesions.Methods: This cross-sectional study included the following groups: (1) normal pregnancy (n = 68); (2) PE (n= 128); and (3) SGA (n = 56). Maternal plasma TF and TFPI activity was determined with chromogenic assays.Results: (1) The median maternal plasma TF activity, but not TFPI activity, differed among the study groups (p < .0001 and p = .4, respectively); (2) patients with PE had a higher median maternal plasma TF activity than women with normal pregnancies (p < .0001) and mothers with SGA fetuses (p = .002); (3) among patients with PE, those with distal villous hypoplasia had a higher median maternal TF activity than those without these placental lesions (p = .018); and (4) following adjustment for confounding variables, maternal plasma TF and TFPI activity were not associated with an SGA neonate.Conclusions: Plasma TF activity is higher in women with PE than in those with SGA or normal pregnancies. We propose that these changes may be responsible, at least in part, for the increased in-vivo thrombin generation observed in this obstetrical syndrome. [ABSTRACT FROM AUTHOR]

Problem: Inflammasomes are signaling platforms that, upon sensing pathogens and sterile stressors, mediate the release of mature forms of interleukin (IL)‐1β and IL‐18. The aims of this study were to determine (i) the expression of major inflammasome components in the chorioamniotic membranes in spontaneous labor at term, (ii) whether there are changes in the inflammasome components associated with the activation of caspase‐1 and caspase‐4, and (iii) whether these events are associated with the release of the mature forms of IL‐1β and IL‐18. Method of study: Chorioamniotic membranes were collected from women at term with and without spontaneous labor. mRNA abundance and protein concentrations of inflammasome components, nucleotide‐binding oligomerization domain‐containing (NOD)1 and NOD2 proteins, caspase‐1, caspase‐4, IL‐1β, and IL‐18 were quantified by qRT‐PCR (n = 28–29 each), ELISA (n = 10 each) or immunoblotting (n = 8 each), and immunohistochemistry (n = 10 each). Active caspase‐1 and caspase‐4, as well as mature IL‐18, were determined by immunoblotting (n = 4 each), and pro‐ and mature forms of IL‐1β were determined by ELISA (n = 4–7 each). Results: Inflammasome components and NOD proteins were expressed in the chorioamniotic membranes obtained from women at term. The chorioamniotic membranes from women who underwent labor had (i) higher concentrations of NLRP3 (NOD‐like receptor family, pyrin domain‐containing protein 3) and NOD1 protein, (ii) greater immunoreactivity for caspase‐1 and caspase‐4, (iii) a greater quantity of the active form of caspase‐1 (p20), and (iv) higher mRNA abundance and protein concentrations of pro‐ and mature IL‐1β. However, mRNA abundance and protein concentrations of the mature form of IL‐18 were not increased in tissues from women who underwent labor at term. Conclusions: Spontaneous labor at term is characterized by the expression of inflammasome components, which may participate in the activation of caspase‐1 and lead to the cleavage and release of mature IL‐1β by the chorioamniotic membranes. These results support the participation of the inflammasome in the mechanisms responsible for spontaneous parturition at term. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the magnetic susceptibility, ∆χ v , as a surrogate marker of venous blood oxygen saturation, S v O 2, in second- and third-trimester normal human foetuses.Methods: Thirty-six pregnant women, having a mean gestational age (GA) of 31 2/7 weeks, underwent magnetic resonance imaging (MRI). Susceptibility-weighted imaging (SWI) data from the foetal brain were acquired. ∆χ v of the superior sagittal sinus (SSS) was quantified using MR susceptometry from the intra-vascular phase measurements. Assuming the magnetic property of foetal blood, ∆χ do , is the same as that of adult blood, S v O 2 was derived from the measured Δχ v . The variation of ∆χ v and S v O 2, as a function of GA, was statistically evaluated.Results: The mean ∆χ v in the SSS in the second-trimester (n = 8) and third-trimester foetuses (n = 28) was found to be 0.34± 0.06 ppm and 0.49 ±0.05 ppm, respectively. Correspondingly, the derived S v O 2 values were 69.4% ±3.27% and 62.6% ±3.25%. Although not statistically significant, an increasing trend (p = 0.08) in Δχ v and a decreasing trend (p = 0.22) in S v O 2 with respect to advancing gestation was observed.Conclusion: We report cerebral venous blood magnetic susceptibility and putative oxygen saturation in healthy human foetuses. Cerebral oxygen saturation in healthy human foetuses, despite a slight decreasing trend, does not change significantly with advancing gestation.Key Points: • Cerebral venous magnetic susceptibility and oxygenation in human foetuses can be quantified. • Cerebral venous oxygenation was not different between second- and third-trimester foetuses. • Foetal cerebral venous oxygenation does not change significantly with advancing gestation. [ABSTRACT FROM AUTHOR]

Objective:Among patients presenting with preterm labor and intact membranes, those with intra-amniotic inflammation have adverse obstetrical and neonatal outcomes. The diagnosis of intra-amniotic inflammation can easily be made by detecting an elevated concentration of the cytokine interleukin (IL)-6 or the enzyme neutrophil collagenase, also known as matrix metalloproteinase (MMP)-8. The diagnostic performances of MMP-8 and IL-6 enzyme-linked immunosorbent assay tests are similar. Recently, a rapid test has become available for point-of-care determination of either MMP-8 or IL-6. The objectives of this study were to compare the diagnostic indices and predictive values between the rapid MMP-8 and IL-6 tests for the identification of intra-amniotic inflammation in patients with preterm labor and intact membranes. Materials and methods:We performed a retrospective cohort study including 124 women with singleton pregnancies who presented with symptoms of preterm labor and underwent transabdominal amniocentesis for the evaluation of microbial invasion of the amniotic cavity (MIAC). MIAC was defined according to amniotic fluid culture results (aerobic and anaerobic bacteria as well as genitalMycoplasmas). Amniotic fluid white blood cell (WBC) counts were determined using a hemocytometer chamber. An elevated amniotic fluid MMP-8 concentration was assessed using Yoon’s MMP-8 Check®(cutoff: 10 ng/mL). An elevated amniotic fluid IL-6 concentration was scored when there was a positive result for the lateral flow-based immunoassay (cutoff: ≥745 pg/mL and ≥1000 pg/mL). In order to objectively compare rapid MMP-8 and rapid IL-6 tests to identify intra-amniotic inflammation, an amniotic fluid WBC count of ≥50 cells/mm3was used to define intra-amniotic inflammation. Results:(1) The rapid tests had the same sensitivity for the detection of intra-amniotic inflammation [85.7% (18/21) for all]; (2) the specificity of the rapid MMP-8 test was higher than that of the rapid IL-6 test (cutoff: 745 pg/mL) for the identification of intra-amniotic inflammation [72.8% (75/103) vs. 64.1% (66/103); p < 0.05]; and (3) there were no differences in the sensitivity and specificity between the rapid MMP-8 test and the rapid IL-6 test (cutoff:1000 pg/mL) in the identification of intra-amniotic inflammation. Of 13 patients with discrepant results between the rapid MMP-8 and rapid IL-6 tests, two had a positive MMP-8 but a negative rapid IL-6 test, and both delivered preterm – one within 24 h, and the other within 10 days – and both had acute histologic chorioamnionitis. On the other hand, there were 11 patients with a positive rapid IL-6 but a negative rapid MMP-8 result: 10 delivered preterm, 3 had acute histologic chorioamnionitis and 1 had subacute chorionitis. Conclusion:We conclude that the rapid MMP-8 test has a better specificity than the rapid IL-6 (cutoff: 745 pg/mL) assay for the detection of intra-amniotic infection. Moreover, we observed that among patients who were not identified as having intra-amniotic infection or inflammation by the standard cultivation technique and amniotic fluid WBC count, those who had a positive MMP-8 rapid test delivered preterm and had acute histologic chorioamnionitis. [ABSTRACT FROM AUTHOR]

Inflammasomes are cytosolic multiprotein complexes that orchestrate inflammation in response to pathogens and endogenous danger signals. Herein, we determined whether the chorioamniotic membranes from women in spontaneous preterm labor with acute histologic chorioamnionitis (1) express major inflammasome components; (2) express caspase (CASP)-1 and CASP-4 as well as their active forms; (3) exhibit apoptosis-associated speck-like protein containing a CARD (ASC)/CASP-1 complex formation; and (4) release the mature forms of interleukin (IL)-1β and IL-18. We utilized quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, immunoblotting, and immunohistochemistry to determine the messenger RNA (mRNA) and protein expression of major inflammasome components, nucleotide-binding oligomerization domain (NOD) proteins, and the pro- and mature/active forms of CASP-1, CASP-4, IL-1β, and IL-18. The ASC/CASP-1 complex formation was determined using an in situ proximity ligation assay. When comparing the chorioamniotic membranes from women in spontaneous preterm labor with acute histologic chorioamnionitis to those without this placental lesion, we found that (1) the mRNA of NLR family pyrin domain-containing protein (NLRP)1, NLRP3, NLR family CARD domain-containing protein 4 (NLRC4), and NOD2 were higher; (2) the NLRP3 protein was increased; (3) the mRNA and active form (p10) of CASP-1 were greater; (4) the mRNA and active form of CASP-4 were increased; (5) the mRNA and mature form of IL-1β were higher; (6) the mature form of IL-18 was elevated; and (7) ASC/CASP-1 complex formation was increased. In conclusion, spontaneous preterm labor with acute histologic chorioamnionitis is characterized by an upregulation of NLRP3 and the active form of CASP-4, as well as increased ASC/CASP-1 complex formation, which may participate in the activation of CASP-1 and the maturation of IL-1β and IL-18 in the chorioamniotic membranes. These findings provide the first evidence that supports a role for the inflammasome in the pathological inflammation implicated in spontaneous preterm labor with acute histologic chorioamnionitis. [ABSTRACT FROM AUTHOR]

Problem To determine whether amniotic fluid ( AF) CXCL10 concentration is associated with histologic chronic chorioamnionitis in patients with preterm labor ( PTL) and preterm prelabor rupture of the membranes ( PROM). Method of Study This study included 168 women who had an episode of PTL or preterm PROM. AF interleukin (IL)-6 and CXCL10 concentrations were determined by immunoassay. Results (i) Increased AF CXCL10 concentration was associated with chronic ( OR: 4.8; 95% CI: 1.7-14), but not acute chorioamnionitis; (ii) increased AF IL-6 concentration was associated with acute ( OR: 4.2; 95% CI: 1.3-13.7) but not chronic chorioamnionitis; and (iii) an increase in AF CXCL10 concentration was associated with placental lesions consistent with maternal anti-fetal rejection ( OR: 3.7; 95% CI: 1.3-10.4). (iv) All patients with elevated AF CXCL10 and IL-6 delivered preterm. Conclusion Increased AF CXCL10 concentration is associated with chronic chorioamnionitis or maternal anti-fetal rejection, whereas increased AF IL-6 concentration is associated with acute histologic chorioamnionitis. [ABSTRACT FROM AUTHOR]

Inflammasomes are cytosolic signaling platforms that regulate the activation of caspase (CASP)-1, which induces the maturation of interleukin (IL)-1β and IL-18. Herein, we determined whether the chorioamniotic membranes from women in spontaneous labor at term with acute histologic chorioamnionitis express major inflammasome components and whether these changes are associated with the activation of CASP-1 and CASP-4 and the release of mature IL-1β and IL-18. When comparing the chorioamniotic membranes from women in spontaneous labor at term with acute histologic chorioamnionitis to those without this placental lesion, we found that (1) the messenger RNA (mRNA) abundance of NLR family pyrin domain containing 3 (NLRP3), NLR family CARD domain containing 4 (NLRC4), absent in melanoma 2 (AIM2), and nucleotide binding oligomerization domain 2 (NOD2) was higher; (2) the NLRP3 and NLRC4 protein quantities were increased; (3) the mRNA and protein expressions of CASP-1 and its active forms were greater; (4) CASP-4 was increased at the mRNA level only; (5) the mRNA and protein expressions of IL-1β and its mature form were higher; and (6) a modest increase in the total protein concentration and abundance of the mature form of IL-18 was observed. In vitro incubation of the chorioamniotic membranes with the CASP-1 inhibitor, VX765, decreased the release of endotoxin-induced IL-1β and IL-18 (2-fold) but not IL-6 or tumor necrosis factor α. In conclusion, spontaneous labor at term with acute histologic chorioamnionitis is characterized by an upregulation of inflammasome components which, in turn, may participate in the activation of CASP-1 and lead to the release of mature IL-1β by the chorioamniotic membranes. These results support a role for the inflammasome in the mechanisms responsible for spontaneous labor at term with acute histologic chorioamnionitis. [ABSTRACT FROM AUTHOR]

Objective: Among patients presenting with preterm labor and intact membranes, those with intra-amniotic inflammation have adverse obstetrical and neonatal outcomes. The diagnosis of intra-amniotic inflammation can easily be made by detecting an elevated concentration of the cytokine interleukin (IL)-6 or the enzyme neutrophil collagenase, also known as matrix metalloproteinase (MMP)-8. The diagnostic performances of MMP-8 and IL-6 enzyme-linked immunosorbent assay tests are similar. Recently, a rapid test has become available for point-of-care determination of either MMP-8 or IL-6. The objectives of this study were to compare the diagnostic indices and predictive values between the rapid MMP-8 and IL-6 tests for the identification of intra-amniotic inflammation in patients with preterm labor and intact membranes.Materials and Methods: We performed a retrospective cohort study including 124 women with singleton pregnancies who presented with symptoms of preterm labor and underwent transabdominal amniocentesis for the evaluation of microbial invasion of the amniotic cavity (MIAC). MIAC was defined according to amniotic fluid culture results (aerobic and anaerobic bacteria as well as genital Mycoplasmas). Amniotic fluid white blood cell (WBC) counts were determined using a hemocytometer chamber. An elevated amniotic fluid MMP-8 concentration was assessed using Yoon's MMP-8 Check® (cutoff: 10 ng/mL). An elevated amniotic fluid IL-6 concentration was scored when there was a positive result for the lateral flow-based immunoassay (cutoff: ≥745 pg/mL and ≥1000 pg/mL). In order to objectively compare rapid MMP-8 and rapid IL-6 tests to identify intra-amniotic inflammation, an amniotic fluid WBC count of ≥50 cells/mm3 was used to define intra-amniotic inflammation.Results: (1) The rapid tests had the same sensitivity for the detection of intra-amniotic inflammation [85.7% (18/21) for all]; (2) the specificity of the rapid MMP-8 test was higher than that of the rapid IL-6 test (cutoff: 745 pg/mL) for the identification of intra-amniotic inflammation [72.8% (75/103) vs. 64.1% (66/103); p < 0.05]; and (3) there were no differences in the sensitivity and specificity between the rapid MMP-8 test and the rapid IL-6 test (cutoff:1000 pg/mL) in the identification of intra-amniotic inflammation. Of 13 patients with discrepant results between the rapid MMP-8 and rapid IL-6 tests, two had a positive MMP-8 but a negative rapid IL-6 test, and both delivered preterm - one within 24 h, and the other within 10 days - and both had acute histologic chorioamnionitis. On the other hand, there were 11 patients with a positive rapid IL-6 but a negative rapid MMP-8 result: 10 delivered preterm, 3 had acute histologic chorioamnionitis and 1 had subacute chorionitis.Conclusion: We conclude that the rapid MMP-8 test has a better specificity than the rapid IL-6 (cutoff: 745 pg/mL) assay for the detection of intra-amniotic infection. Moreover, we observed that among patients who were not identified as having intra-amniotic infection or inflammation by the standard cultivation technique and amniotic fluid WBC count, those who had a positive MMP-8 rapid test delivered preterm and had acute histologic chorioamnionitis. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the performance of Fetal Intelligent Navigation Echocardiography (FINE) applied to spatiotemporal image correlation (STIC) volume datasets of the normal fetal heart in generating standard fetal echocardiography views.Methods: In this prospective cohort study of patients with normal fetal hearts (19-30 gestational weeks), one or more STIC volume datasets were obtained of the apical four-chamber view. Each STIC volume successfully obtained was evaluated by STICLoop™ to determine its appropriateness before applying the FINE method. Visualization rates for standard fetal echocardiography views using diagnostic planes and/or Virtual Intelligent Sonographer Assistance (VIS-Assistance®) were calculated.Results: One or more STIC volumes (total n = 463) were obtained from 246 patients. A single STIC volume per patient was analyzed using the FINE method. In normal cases, FINE was able to generate nine fetal echocardiography views using: (1) diagnostic planes in 76-100% of the cases, (2) VIS-Assistance® in 96-100% of the cases, and (3) a combination of diagnostic planes and/or VIS-Assistance® in 96-100% of the cases.Conclusion: FINE applied to STIC volumes can successfully generate nine standard fetal echocardiography views in 96-100% of cases in the 2nd and 3rd trimesters. This suggests that the technology can be used as a method of screening for congenital heart disease. [ABSTRACT FROM AUTHOR]

Magnetic resonance angiography has not been used much previously for visualizing fetal vessels in utero for reasons that include a contraindication for the use of exogenous contrast agents, maternal respiratory motion and fetal motion. In this work, we report the feasibility of using an appropriately modified clinical time-of-flight magnetic resonance imaging sequence for non-contrast angiography of human fetal and placental vessels at 3.0 T. Using this 2D angiography technique, it is possible to visualize fetal vascular networks in late pregnancy.Key Points: • 3D-visualization of fetal vasculature is feasible using non-contrast MRA at 3.0 T. • Visualization of placental vasculature is also possible with this method. • Fetal MRA can serve as a vascular localizer for quantitative MRI studies. • This method can be extended to 1.5 T. [ABSTRACT FROM AUTHOR]

Objectives: To assess the value of single and serial fetal biometry for the prediction of small- (SGA) and large-for-gestational-age (LGA) neonates delivered preterm or at term. Methods: A cohort study of 3,971 women with singleton pregnancies was conducted from the first trimester until delivery with 3,440 pregnancies (17,334 scans) meeting the following inclusion criteria: 1) delivery of a live neonate after 33 gestational weeks and 2) two or more ultrasound examinations with fetal biometry parameters obtained at ≤36 weeks. Primary outcomes were SGA (<5th centile) and LGA (>95th centile) at birth based on INTERGROWTH-21st gender-specific standards. Fetus-specific estimated fetal weight (EFW) trajectories were calculated by linear mixed-effects models using data up to a fixed gestational age (GA) cutoff (28, 32, or 36 weeks) for fetuses having two or more measurements before the GA cutoff and not already delivered. A screen test positive for single biometry was based on Z-scores of EFW at the last scan before each GA cut-off so that the false positive rate (FPR) was 10%. Similarly, a screen test positive for the longitudinal analysis was based on the projected (extrapolated) EFW at 40 weeks from all available measurements before each cutoff for each fetus. Results: Fetal abdominal and head circumference measurements, as well as birth weights in the Detroit population, matched well to the INTERGROWTH-21st standards, yet this was not the case for biparietal diameter (BPD) and femur length (FL) (up to 9% and 10% discrepancy for mean and confidence intervals, respectively), mainly due to differences in the measurement technique. Single biometry based on EFW at the last scan at ≤32 weeks (GA IQR: 27.4–30.9 weeks) had a sensitivity of 50% and 53% (FPR = 10%) to detect preterm and term SGA and LGA neonates, respectively (AUC of 82% both). For the detection of LGA using data up to 32- and 36-week cutoffs, single biometry analysis had higher sensitivity than longitudinal analysis (52% vs 46% and 62% vs 52%, respectively; both p<0.05). Restricting the analysis to subjects with the last observation taken within two weeks from the cutoff, the sensitivity for detection of LGA, but not SGA, increased to 65% and 72% for single biometry at the 32- and 36-week cutoffs, respectively. SGA screening performance was higher for preterm (<37 weeks) than for term cases (73% vs 46% sensitivity; p<0.05) for single biometry at ≤32 weeks. Conclusions: When growth abnormalities are defined based on birth weight, growth velocity (captured in the longitudinal analysis) does not provide additional information when compared to the last measurement for predicting SGA and LGA neonates, with both approaches detecting one-half of the neonates (FPR = 10%) from data collected at ≤32 weeks. Unlike for SGA, LGA detection can be improved if ultrasound scans are scheduled as close as possible to the gestational-age cutoff when a decision regarding the clinical management of the patient needs to be made. Screening performance for SGA is higher for neonates that will be delivered preterm. [ABSTRACT FROM AUTHOR]

Objective: To determine (1) whether maternal plasma concentrations of angiogenic and anti-angiogenic factors can predict which mothers diagnosed with “suspected small for gestational age fetuses (sSGA)” will develop pre-eclampsia (PE) or require an indicated early preterm delivery (≤ 34 weeks of gestation); and (2) whether risk assessment performance is improved using these proteins in addition to clinical factors and Doppler parameters. Methods: This prospective cohort study included women with singleton pregnancies diagnosed with sSGA (estimated fetal weight <10th percentile) between 24 and 34 weeks of gestation (n = 314). Plasma concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), soluble endoglin (sEng) and placental growth factor (PlGF) were determined in maternal blood obtained at the time of diagnosis. Doppler velocimetry of the umbilical (Umb) and uterine (UT) arteries was performed. The outcomes were (1) subsequent development of PE; and (2) indicated preterm delivery at ≤34 weeks of gestation (excluding deliveries as a result of spontaneous preterm labor, preterm pre-labor rupture of membranes or chorioamnionitis). Results: (1) The prevalence of PE and indicated preterm delivery was 9.2% (n = 29/314) and 7.3% (n = 23/314), respectively; (2) the area under the receiver operating characteristic curve (AUC) for the identification of patients who developed PE and/or required indicated preterm delivery was greater than 80% for the UT artery pulsatility index (PI)z-score and each biochemical marker (including their ratios) except sVEGFR-1 MoM; (3) using cutoffs at a false positive rate of 15%, women with abnormal plasma concentrations of angiogenic/anti-angiogenic factors were 7–13 times more likely to develop PE, and 12–22 times more likely to require preterm delivery than those with normal plasma MoM concentrations of these factors; (4) sEng, PlGF, PIGF/sEng and PIGF/sVEGFR-1 ratios MoM, each contributed significant information about therisk of PEbeyond that provided by clinical factors and/or Doppler parameters: women who had low MoM values for these biomarkers were at 5–9 times greater risk of developing PE than women who had normal values, adjusting for clinical factors and Doppler parameters (adjusted odds ratio for PlGF: 9.1, PlGF/sEng: 5.6); (5) the concentrations of sVEGFR-1 and PlGF/sVEGFR-1 ratio MoM, each contributed significant information about therisk of indicated preterm deliverybeyond that provided by clinical factors and/or Doppler parameters: women who had abnormal values were at 8–9 times greater risk for indicated preterm delivery, adjusting for clinical factors and Doppler parameters; and (6) for a two-stage risk assessment (Umb artery Doppler followed by Ut artery Doppler plus biochemical markers), among women who had normal Umb artery Doppler velocimetry (n = 279), 21 (7.5%) developed PE and 11 (52%) of these women were identified by an abnormal UT artery Doppler mean PIz-score (>2SD): a combination of PlGF/sEng ratio MoM concentration and abnormal UT artery Doppler velocimetry increased the sensitivity of abnormal UT artery Doppler velocimetry to 76% (16/21) at a fixed false-positive rate of 10% (p = 0.06). Conclusion: Angiogenic and anti-angiogenic factors measured in maternal blood between 24 and 34 weeks of gestation can identify the majority of mothers diagnosed with “suspected SGA” who subsequently developed PE or those who later required preterm delivery ≤34 weeks of gestation. Moreover, incorporation of these biochemical markers significantly improves risk assessment performance for these outcomes beyond that of clinical factors and uterine and umbilical artery Doppler velocimetry. [ABSTRACT FROM PUBLISHER]

Massive perivillous fibrin deposition of the placenta (MPFD) or maternal floor infarction (MFI) is a serious condition associated with recurrent complications including fetal death and severe fetal growth restriction. There is no method to evaluate the risk of adverse outcome in subsequent pregnancies, or effective prevention. Recent observations suggest that MFI is characterized by an imbalance in angiogenic/anti-angiogenic factors in early pregnancy; therefore, determination of these biomarkers may identify the patient at risk for recurrence. We report the case of a pregnant woman with a history of four consecutive pregnancy losses, the last of which was affected by MFI. Abnormalities of the anti-angiogenic factor, sVEGFR-1, and soluble endoglin (sEng) were detected early in the index pregnancy, and treatment with pravastatin corrected the abnormalities. Treatment resulted in a live birth infant at 34 weeks of gestation who had normal biometric parameters and developmental milestones at the age of 2. This is the first reported successful use of pravastatin to reverse an angiogenic/anti-angiogenic imbalance and prevent fetal death. [ABSTRACT FROM PUBLISHER]

Objective: Prostaglandins (PGs) are considered the universal mediators of parturition. Amniotic fluid PGE2and PGF2αconcentrations increase before the onset of spontaneous labor at term, as well as during labor. This study was conducted to determine if the concentrations of umbilical cord PGE2and PGF2α change with advancing gestational age, spontaneous labor at term, and preterm labor (with and without funisitis). Methods: Umbilical cord (UC) tissue samples were obtained from women (N = 158) with singleton pregnancies in the following groups: (1) term deliveries without labor (TNL;n = 20); (2) term deliveries with labor (TIL;n = 20); (3) spontaneous preterm deliveries (sPTD) with (n = 20) and without acute funisitis (n = 20); and (4) preeclampsia without labor (n = 78). The concentrations of PGs were determined in different locations of the UC. PGE2and PGF2αwere measured by specific immunoassays. Non-parametric statistics were used for analysis. Results: (1) In spontaneous preterm deliveries, the median UC PGE2concentration was higher in cases with funisitis than in those without funisitis (233.7 pg/µg versus 87.4 pg/µg of total protein,p = 0.001); (2) the median UC PGE2concentration in sPTD with funisitis was also higher than that obtained from samples who had undergone labor at term (233.7 pg/µg versus 116.1 pg/µg of total protein,p = 0.03); (3) the UC PGE2and PGF2αconcentration increased as a function of advancing gestational age before 36 weeks (PGE2: ρ = 0.59,p < 0.001; PGF2α: ρ = 0.39,p = 0.01), but not after 36 weeks (PGE2: ρ = −0.1,p = 0.5; PGF2α: ρ = −0.2,p = 0.2); (4) the median UC concentrations of PGE2and PGF2αat term was similar in samples obtained from women with and without labor (PGE2: TNL 133.7 pg/µg versus TIL 116.1 pg/µg of total protein,p = 0.9; PGF2α: TNL 8.4 pg/µg versus TIL 8.1 pg/µg of total protein,p = 0.7); and (5) there was no correlation between UC PG concentration and gestational age at term pregnancy (PGE2: ρ = 0.01,p = 0.9; PGF2α: ρ = 0.07,p = 0.7). Conclusions: (1) PGE2concentrations in the UC are higher in the presence of acute funisitis than in the absence of this lesion; (2) spontaneous labor at term was not associated with a change in the UC concentration of PGE2and PGF2α; and (3) the UC concentrations of PGE2and PGF2αincreased as a function of gestational age. We propose that UC PGs act as inflammatory mediators generated in the context of fetal systemic inflammation. [ABSTRACT FROM PUBLISHER]

Objective: Preterm prelabor rupture of membranes (preterm PROM) accounts for 30-40% of spontaneous preterm deliveries and thus is a major contributor to perinatal morbidity and mortality. An amniotic fluid (AF) interleukin-6 (IL-6) concentration is a key cytokine for the identification of intra-amniotic inflammation, patients at risk of impending preterm delivery and adverse pregnancy complications. The conventional method to determine IL-6 concentrations in AF is an enzyme-linked immunosorbent assay (ELISA). However, this technique is not available in clinical settings, and the results may take several days. A lateral flow-based immunoassay, or point of care (POC) test, has been developed to address this issue. The objective of this study was to compare the performance of AF IL-6 determined by the POC test to that determined by ELISA for the identification of intra-amniotic inflammation in patients with preterm PROM.Materials and Methods: This retrospective cohort study includes 56 women with singleton pregnancies who presented with preterm PROM. Amniocentesis was performed at the time of diagnosis, and AF was analyzed using cultivation techniques for aerobic and anaerobic bacteria as well as genital mycoplasmas. AF Gram stain and AF white blood cell counts were determined. AF IL-6 concentrations were measured using both lateral flow-based immunoassay and ELISA. The primary outcome was intra-amniotic inflammation defined as AF ELISA IL-6 ≥ 2600 pg/ml. A previously determined cut-off of 745 pg/ml was used to define a positive POC test.Results: (1) The POC test for AF IL-6 concentrations had 97% sensitivity and 96% specificity for the identification of intra-amniotic inflammation, as defined using ELISA among patients with preterm PROM and (2) the diagnostic performance of the POC test for IL-6 was strongly correlated to that of an ELISA test for the identification of intra-amniotic inflammation and was equivalent for the identification of acute inflammatory placental lesions and microbial invasion of the amniotic cavity (MIAC).Conclusion: A POC AF IL-6 test can identify intra-amniotic inflammation in patients with preterm PROM. Results can be available within 20 min - this makes it possible to implement interventions designed to treat intra-amniotic inflammation and improve pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Objective: Preterm birth is associated with 5-18% of pregnancies and is the leading cause of neonatal morbidity and mortality. Amniotic fluid (AF) interleukin-6 (IL-6) is a key cytokine for the identification of intra-amniotic inflammation, and patients with an elevated AF IL-6 are at risk for impending preterm delivery. However, results of the conventional method of measurement (enzyme-linked immunosorbent assay; ELISA) are usually not available in time to inform care. The objective of this study was to determine whether a point of care (POC) test or lateral-flow-based immunoassay for measurement of AF IL-6 concentrations can identify patients with intra-amniotic inflammation and/or infection and those destined to deliver spontaneously before term among women with preterm labor and intact membranes.Methods: One-hundred thirty-six women with singleton pregnancies who presented with symptoms of preterm labor and underwent amniocentesis were included in this study. Amniocentesis was performed at the time of diagnosis of preterm labor. AF Gram stain and AF white blood cell counts were determined. Microbial invasion of the amniotic cavity (MIAC) was defined according to the results of AF culture (aerobic and anaerobic as well as genital mycoplasmas). AF IL-6 concentrations were determined by both lateral flow-based immunoassay and ELISA. The primary outcome was intra-amniotic inflammation, defined as AF ELISA IL-6 ≥ 2600 pg/ml.Results: (1) AF IL-6 concentrations determined by a POC test have high sensitivity (93%), specificity (91%) and a positive likelihood ratio of 10 for the identification of intra-amniotic inflammation by using a threshold of 745 pg/ml; (2) the POC test and ELISA for IL-6 perform similarly in the identification of MIAC, acute inflammatory lesions of placenta and patients at risk of impending spontaneous preterm delivery.Conclusion: A POC AF IL-6 test can identify intra-amniotic inflammation in women who present with preterm labor and intact membranes and those who will subsequently deliver spontaneously before 34 weeks of gestation. Results can be available within 20 min - this has important clinical implications and opens avenues for early diagnosis as well as treatment of intra-amniotic inflammation/infection. [ABSTRACT FROM AUTHOR]

Objective: To compare third-trimester size trajectory prediction errors (average transformed percent deviations) for three individualized fetal growth assessment methods.Methods: This study utilized longitudinal measurements of nine directly measured size parameters in 118 fetuses with normal neonatal growth outcomes. Expected value (EV) function coefficients and variance components were obtained using two-level random coefficient modeling. Growth models (IGA) or EV coefficients and variance components (PLM and CPM) were used to calculate predicted values at ∼400 third-trimester time points. Percent deviations (%Dev) calculated at these time points using all three methods were expressed as percentages of IGA MA-specific reference ranges [transformed percent deviations (T%Dev)]. Third-trimester T%Dev values were averaged (aT%Dev) for each parameter. Mean ± standard deviation's for sets of aT%Dev values derived from each method (IGA, PLM and CPM) were calculated and compared.Results: Mean aT%Dev values for nine parameters were: (i) IGA: -4.3 to 5.2% (9/9 not different from zero); (ii) PLM: -32.7 to 25.6% (4/9 not different from zero) and (iii) CPM: -20.4 to 17.4% (5/9 not different from zero). Seven of nine systematic deviations from zero were statistically significant when IGA values were compared to either PLM or CPM values. Variabilities were smaller for IGA when compared to those for PLM or CPM, with (i) 5/9 being statistically significant (IGA versus PLM), (ii) 2/9 being statistically significant (IGA versus CPM) and (iii) 5/9 being statistically significant (PLM versus CPM).Conclusions: Significant differences in the agreement between predicted third-trimester size parameters and their measured values were found for the three methods tested. With most parameters, IGA gave smaller mean aT%Dev values and smaller variabilities. The CPM method was better than the PLM approach for most but not all parameters. These results suggest that third-trimester size trajectories are best characterized by IGA in fetuses with normal growth outcomes. [ABSTRACT FROM AUTHOR]

Objective: The diagnosis of clinical chorioamnionitis is based on a combination of signs [fever, maternal or fetal tachycardia, foul-smelling amniotic fluid (AF), uterine tenderness and maternal leukocytosis]. Bacterial infections within the amniotic cavity are considered the most frequent cause of clinical chorioamnionitis and an indication for antibiotic administration to reduce maternal and neonatal morbidity. Recent studies show that only 54% of patients with the diagnosis of clinical chorioamnionitis at term have bacteria in the AF and evidence of intra-amniotic inflammation. The objective of this study was to examine the performance of the clinical criteria for the diagnosis of chorioamnionitis to identify patients with microbial-associated intra-amniotic inflammation (also termed intra-amniotic infection). Materials and methods: This retrospective cross-sectional study included 45 patients with the diagnosis of clinical chorioamnionitis at term, whose AF underwent analysis for: 1) the presence of microorganisms using both cultivation and molecular biologic techniques [polymerase chain reaction (PCR) with broad primers], and 2) interleukin (IL)-6 concentrations by enzyme-linked immunosorbent assay. The diagnostic performance (sensitivity, specificity, accuracy, and likelihood ratios) of each clinical sign and their combination to identify clinical chorioamnionitis were determined using microbial-associated intra-amniotic inflammation [presence of microorganisms in the AF using cultivation or molecular techniques and elevated AF IL-6 concentrations (≥2.6 ng/mL)] as the gold standard. Results: The accuracy of each clinical sign for the identification of microbial-associated intra-amniotic inflammation (intra-amniotic infection) ranged between 46.7% and 57.8%. The combination of fever with three or more clinical criteria did not substantially improve diagnostic accuracy. Conclusion: In the presence of a fever during labor at term, signs used to diagnose clinical chorioamnionitis do not accurately identify the patient with proven intra-amniotic infection (i.e., those with microorganisms detected by culture or molecular microbiologic techniques and an associated intra-amniotic inflammatory response). [ABSTRACT FROM AUTHOR]

Objective: Recent studies indicate that clinical chorioamnionitis is a heterogeneous condition and only approximately one-half of the patients have bacteria in the amniotic cavity, which is often associated with intra-amniotic inflammation. The objective of this study is to characterize the nature of the inflammatory response within the amniotic cavity in patients with clinical chorioamnionitis at term according to the presence or absence of 1) bacteria in the amniotic cavity and 2) intra-amniotic inflammation. Materials and methods: A retrospective cross-sectional case-control study was conducted to examine cytokine and chemokine concentrations in the amniotic fluid (AF). Cases consisted of women with clinical chorioamnionitis at term (n=45). Controls were women with uncomplicated pregnancies at term who did not have intra-amniotic inflammation and were in labor (n=24). Women with clinical chorioamnionitis were classified according to the results of AF cultures, broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry, and AF concentration of interleukin-6 (IL-6) into those: 1) without intra-amniotic inflammation, 2) with microbial-associated intra-amniotic inflammation, and 3) with intra-amniotic inflammation without detectable bacteria. The AF concentrations of 29 cytokines/chemokines were determined using sensitive and specific V-PLEX immunoassays. Results: 1) The AF concentrations of pro- and anti-inflammatory cytokines/chemokines such as interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin-4 (IL-4), macrophage inflammatory protein-1 beta (MIP-1β), and interleukin-8 (IL-8) (except Eotaxin-3) were significantly higher in women with clinical chorioamnionitis at term than in controls (term labor without intra-amniotic inflammation); 2) patients with microbial-associated intra-amniotic inflammation, and those with intra-amniotic inflammation without detectable bacteria, had a dramatic differential expression of cytokines and chemokines in AF compared to patients with spontaneous labor without intra-amniotic inflammation. However, no difference could be detected in the pattern of the intra-amniotic inflammatory response between patients with intra-amniotic inflammation with and without detectable bacteria; and 3) in patients with clinical chorioamnionitis at term but without intra-amniotic inflammation, the behavior of cytokines and chemokines in the AF was similar to those in spontaneous labor at term. Conclusions: Patients with clinical chorioamnionitis who had microbial-associated intra-amniotic inflammation or intra-amniotic inflammation without detectable bacteria had a dramatic upregulation of the intra-amniotic inflammatory response assessed by amniotic fluid concentrations of cytokines. A subset of patients with term clinical chorioamnionitis does not have intra-amniotic infection/inflammation, as demonstrated by elevated AF concentrations of inflammation-related proteins, when compared to women in term labor with uncomplicated pregnancies, suggesting over-diagnosis. These observations constitute the first characterization of the cytokine/chemokine network in the amniotic cavity of patients with clinical chorioamnionitis at term. [ABSTRACT FROM AUTHOR]

Introduction: Fever is a major criterion for clinical chorioamnionitis; yet, many patients with intrapartum fever do not have demonstrable intra-amniotic infection. Some cytokines, such as interleukin (IL)-1, IL-6, interferon-gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α), can induce a fever. The objective of this study was to determine whether maternal plasma concentrations of cytokines could be of value in the identification of patients with the diagnosis of clinical chorioamnionitis at term who have microbial-associated intra-amniotic inflammation. Methods: A retrospective cross-sectional study was conducted, including patients with clinical chorioamnionitis at term (n=41; cases) and women in spontaneous labor at term without clinical chorioamnionitis (n=77; controls). Women with clinical chorioamnionitis were classified into three groups according to the results of amniotic fluid culture, broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS), and amniotic fluid IL-6 concentration: 1) no intra-amniotic inflammation; 2) intra-amniotic inflammation without detectable microorganisms; or 3) microbial-associated intra-amniotic inflammation. The maternal plasma concentrations of 29 cytokines were determined with sensitive and specific V-PLEX immunoassays. Nonparametric statistical methods were used for analysis, adjusting for a false discovery rate of 5%. Results: 1) The maternal plasma concentrations of pyrogenic cytokines (IL-1β, IL-2, IL-6, IFN-γ, and TNF-α) were significantly higher in patients with clinical chorioamnionitis at term than in those with spontaneous term labor without clinical chorioamnionitis; 2) the maternal plasma concentrations of cytokines were not significantly different among the three subgroups of patients with clinical chorioamnionitis (intra-amniotic inflammation with and without detectable bacteria and those without intra-amniotic inflammation); and 3) among women with the diagnosis of clinical chorioamnionitis, but without evidence of intra-amniotic inflammation, the maternal plasma concentrations of pyrogenic cytokines were significantly higher than in patients with spontaneous labor at term. These observations suggest that a fever can be mediated by increased circulating concentrations of these cytokines, despite the absence of a local intra-amniotic inflammatory response. Conclusions: 1) The maternal plasma concentrations of pyrogenic cytokines (e.g. IL-1β, IL-2, IL-6, IFN-γ, and TNF-α) are higher in patients with intra-partum fever and the diagnosis of clinical chorioamnionitis at term than in those in spontaneous labor at term without a fever; and 2) maternal plasma cytokine concentrations have limited value in the identification of patients with bacteria in the amniotic cavity. Accurate assessment of the presence of intra-amniotic infection requires amniotic fluid analysis. [ABSTRACT FROM AUTHOR]

Objective: Neonates born to mothers with clinical chorioamnionitis at term are at an increased risk of infection. Acute subchorionitis, chorioamnionitis, and funisitis are considered placental histologic features consistent with acute inflammation according to the Society for Pediatric Pathology. The objectives of this study were to examine the performance of placental histologic features in the identification of: 1) microbial-associated intra-amniotic inflammation (intra-amniotic infection); and 2) fetal inflammatory response syndrome (FIRS). Methods: This retrospective cohort study included women with the diagnosis of clinical chorioamnionitis at term (n=45), who underwent an amniocentesis to determine: 1) the presence of microorganisms using both cultivation and molecular biologic techniques [polymerase chain reaction (PCR) with broad range primers]; and 2) interleukin (IL)-6 concentrations by enzyme-linked immunosorbent assay (ELISA). The diagnostic performance (sensitivity, specificity, accuracy, and likelihood ratios) of placental histologic features consistent with acute inflammation was determined for the identification of microbial-associated intra-amniotic inflammation and FIRS. Results: 1) The presence of acute histologic chorioamnionitis and funisitis was associated with the presence of proven intra-amniotic infection assessed by amniotic fluid analysis; 2) funisitis was also associated with the presence of FIRS; 3) the negative predictive value of acute funisitis ≥stage 2 for the identification of neonates born to mothers with intra-amniotic infection was <50%, and therefore, suboptimal to exclude fetal exposure to bacteria in the amniotic cavity; and 4) acute funisitis ≥stage 2 had a negative predictive value of 86.8% for the identification of FIRS in a population with a prevalence of 20%. Conclusion: Acute histologic chorioamnionitis and funisitis are associated with intra-amniotic infection and the presence of FIRS. However, current pathologic methods have limitations in the identification of the fetus exposed to microorganisms present in the amniotic cavity. Further studies are thus required to determine whether molecular markers can enhance the performance of placental pathology in the identification of neonates at risk for neonatal sepsis. [ABSTRACT FROM AUTHOR]