Role of recombinant factor VIIa in the clinical management of severe postpartum hemorrhage: consensus among European experts.

OBJECTIVES: There have been significant advances in the medical management of severe postpartum hemorrhage (sPPH) over recent decades, which is reflected in numerous published guidelines. To date, many of the currently available national and international guidelines recommend recombinant factor VIIa (rFVIIa) to be used only at a very late stage in the course of sPPH, as a "last resort", before or after hysterectomy. Based on new safety data, rFVIIa has recently been approved by the European Medicines Agency (EMA) and Swissmedic for use in sPPH, if uterotonics are insufficient to achieve hemostasis, which in fact is significantly earlier in the course of postpartum hemorrhage (PPH). We therefore aimed to develop expert consensus guidance as a step toward standardizing care with the use of rFVIIa for clinicians managing women experiencing life-threatening sPPH. METHODS: The consensus process consisted of one face-to-face meeting with a group of nine experts, including eight obstetrician-gynecologists and a hematologist highly experienced in sPPH care in tertiary care perinatal centers. The panel was representative of multidisciplinary expertise in the European obstetrics community and provided consensus opinion in answer to pre-defined questions around clinical practice with rFVIIa in the management of sPPH. Recommendations have been based on current national and international guidelines, extensive clinical experience, and consensus opinion, as well as the availability of efficacy and new safety data. RESULTS: The expert panel developed 17 consensus statements in response to the 13 pre-defined questions on the use of rFVIIa in the management of sPPH including: available efficacy and safety data and the need for interdisciplinary expertise between obstetricians, anesthesiologists, and hematologists in the management of sPPH. Based on novel data, the experts recommend: (1) earlier administration of rFVIIa in patients with sPPH who do not respond to uterotonic administration to optimize the efficacy of rFVIIa; (2) the importance of hematological parameter prerequisites prior to the administration of rFVIIa to maximize efficacy; and (3) continued evaluation or initiation of further invasive procedures according to standard practice. Furthermore, recommendations on the timing of rFVIIa treatment within the sPPH management algorithm are outlined in a range of specified clinical scenarios and settings, including vaginal delivery, cesarean section, and smaller birthing units before transfer to a tertiary care center. The panel agreed that according to available, and new data, as well as real-world experience, there is no evidence that the use of rFVIIa in patients with sPPH increases the risk of thromboembolism. The authors acknowledge that there is still limited clinical effectiveness data, as well as pharmacoeconomic data, on the use of rFVIIa in sPPH, and recommend further clinical trials and efficacy investigation. CONCLUSIONS: This expert panel provides consensus guidance based on recently available data, clinical experience, and expert opinion, augmented by the recent approval of rFVIIa for use in sPPH by the EMA. These consensus statements are intended to support clinical care for sPPH and may help to provide the impetus and a starting point for updates to existing clinical practice guidelines.

Reduced fetal growth velocity precedes antepartum fetal death.

OBJECTIVES: To determine whether decreased fetal growth velocity precedes antepartum fetal death and to evaluate whether fetal growth velocity is a better predictor of antepartum fetal death compared to a single fetal biometric measurement at the last available ultrasound scan prior to diagnosis of demise. METHODS: This was a retrospective, longitudinal study of 4285 singleton pregnancies in African-American women who underwent at least two fetal ultrasound examinations between 14 and 32 weeks of gestation and delivered a liveborn neonate (controls; n = 4262) or experienced antepartum fetal death (cases; n = 23). Fetal death was defined as death diagnosed at ≥ 20 weeks of gestation and confirmed by ultrasound examination. Exclusion criteria included congenital anomaly, birth at < 20 weeks of gestation, multiple gestation and intrapartum fetal death. The ultrasound examination performed at the time of fetal demise was not included in the analysis. Percentiles for estimated fetal weight (EFW) and individual biometric parameters were determined according to the Hadlock and Perinatology Research Branch/Eunice Kennedy Shriver National Institute of Child Health and Human Development (PRB/NICHD) fetal growth standards. Fetal growth velocity was defined as the slope of the regression line of the measurement percentiles as a function of gestational age based on two or more measurements in each pregnancy. RESULTS: Cases had significantly lower growth velocities of EFW (P < 0.001) and of fetal head circumference, biparietal diameter, abdominal circumference and femur length (all P < 0.05) compared to controls, according to the PRB/NICHD and Hadlock growth standards. Fetuses with EFW growth velocity < 10th percentile of the controls had a 9.4-fold and an 11.2-fold increased risk of antepartum death, based on the Hadlock and customized PRB/NICHD standards, respectively. At a 10% false-positive rate, the sensitivity of EFW growth velocity for predicting antepartum fetal death was 56.5%, compared to 26.1% for a single EFW percentile evaluation at the last available ultrasound examination, according to the customized PRB/NICHD standard. CONCLUSIONS: Given that 74% of antepartum fetal death cases were not diagnosed as small-for-gestational age (EFW < 10th percentile) at the last ultrasound examination when the fetuses were alive, alternative approaches are needed to improve detection of fetuses at risk of fetal death. Longitudinal sonographic evaluation to determine growth velocity doubles the sensitivity for prediction of antepartum fetal death compared to a single EFW measurement at the last available ultrasound examination, yet the performance is still suboptimal. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Prediction of adverse perinatal outcome by fetal biometry: comparison of customized and population-based standards.

OBJECTIVE: To compare the predictive performance of estimated fetal weight (EFW) percentiles, according to eight growth standards, to detect fetuses at risk for adverse perinatal outcome. METHODS: This was a retrospective cohort study of 3437 African-American women. Population-based (Hadlock, INTERGROWTH-21st , World Health Organization (WHO), Fetal Medicine Foundation (FMF)), ethnicity-specific (Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)), customized (Gestation-Related Optimal Weight (GROW)) and African-American customized (Perinatology Research Branch (PRB)/NICHD) growth standards were used to calculate EFW percentiles from the last available scan prior to delivery. Prediction performance indices and relative risk (RR) were calculated for EFW < 10th and > 90th percentiles, according to each standard, for individual and composite adverse perinatal outcomes. Sensitivity at a fixed (10%) false-positive rate (FPR) and partial (FPR < 10%) and full areas under the receiver-operating-characteristics curves (AUC) were compared between the standards. RESULTS: Ten percent (341/3437) of neonates were classified as small-for-gestational age (SGA) at birth, and of these 16.4% (56/341) had at least one adverse perinatal outcome. SGA neonates had a 1.5-fold increased risk of any adverse perinatal outcome (P < 0.05). The screen-positive rate of EFW < 10th percentile varied from 6.8% (NICHD) to 24.4% (FMF). EFW < 10th percentile, according to all standards, was associated with an increased risk for each of the adverse perinatal outcomes considered (P < 0.05 for all). The highest RRs associated with EFW < 10th percentile for each adverse outcome were 5.1 (95% CI, 2.1-12.3) for perinatal mortality (WHO); 5.0 (95% CI, 3.2-7.8) for perinatal hypoglycemia (NICHD); 3.4 (95% CI, 2.4-4.7) for mechanical ventilation (NICHD); 2.9 (95% CI, 1.8-4.6) for 5-min Apgar score < 7 (GROW); 2.7 (95% CI, 2.0-3.6) for neonatal intensive care unit (NICU) admission (NICHD); and 2.5 (95% CI, 1.9-3.1) for composite adverse perinatal outcome (NICHD). Although the RR CIs overlapped among all standards for each individual outcome, the RR of composite adverse perinatal outcome in pregnancies with EFW < 10th percentile was higher according to the NICHD (2.46; 95% CI, 1.9-3.1) than the FMF (1.47; 95% CI, 1.2-1.8) standard. The sensitivity for composite adverse perinatal outcome varied substantially between standards, ranging from 15% for NICHD to 32% for FMF, due mostly to differences in FPR; this variation subsided when the FPR was set to the same value (10%). Analysis of AUC revealed significantly better performance for the prediction of perinatal mortality by the PRB/NICHD standard (AUC = 0.70) compared with the Hadlock (AUC = 0.66) and FMF (AUC = 0.64) standards. Evaluation of partial AUC (FPR < 10%) demonstrated that the INTERGROWTH-21st standard performed better than the Hadlock standard for the prediction of NICU admission and mechanical ventilation (P < 0.05 for both). Although fetuses with EFW > 90th percentile were also at risk for any adverse perinatal outcome according to the INTERGROWTH-21st (RR = 1.4; 95% CI, 1.0-1.9) and Hadlock (RR = 1.7; 95% CI, 1.1-2.6) standards, many times fewer cases (2-5-fold lower sensitivity) were detected by using EFW > 90th percentile, rather than EFW < 10th percentile, in screening by these standards. CONCLUSIONS: Fetuses with EFW < 10th percentile or EFW > 90th percentile were at increased risk of adverse perinatal outcomes according to all or some of the eight growth standards, respectively. The RR of a composite adverse perinatal outcome in pregnancies with EFW < 10th percentile was higher for the most-stringent (NICHD) compared with the least-stringent (FMF) standard. The results of the complementary analysis of AUC suggest slightly improved detection of adverse perinatal outcome by more recent population-based (INTERGROWTH-21st ) and customized (PRB/NICHD) standards compared with the Hadlock and FMF standards. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.

Puerperal ventral epidural hematoma after epidural labor analgesia.

Serious complications in obstetric anesthesia are a rare occurrence. High neuraxial block, respiratory arrest in labor and delivery, and an unrecognized spinal catheter are among the most frequently reported serious complications. A serious complication occurs in approximately 1:3000 obstetric patients. Neuraxial hematoma after obstetric epidural analgesia or anesthesia is extremely rare. We present a case of a puerperal spinal epidural hematoma following epidural labor analgesia. The patient presented with foot drop, which resolved after conservative treatment. We reviewed the epidemiology, clinical manifestations and treatment options for this rare complication.

Maternal First Trimester TSH Concentrations: Do They Affect Perinatal and Endocrine Outcomes?

We aimed to examine the distribution of 1(st) trimester TSH and evaluate its association with perinatal outcomes and future development of maternal thyrotoxicosis. This retrospective cohort study included data of all women without prior thyroid disease who delivered a singleton at our medical center from 1/2001 to 12/2011 and had a 1(st) trimester TSH<4.0 mU/l. Women were divided according to 1(st) trimester TSH concentrations into quartiles and by predefined TSH values (mU/l): 1) TSH<0.1; 2) TSH 0.11-0.2; 3) TSH 0.21-0.4; and 4) TSH 0.4-4. Obstetrical outcomes, hCG concentrations, and future thyroid status were collected from electronic medical records. A total of 13 841 women fulfilled the inclusion criteria. Mean maternal TSH concentration at 5 weeks of gestation was 2.09±0.83 mU/l and decreased to 1.29±0.87 mU/l in weeks 8-9 with an increase towards the end of the 1(st) trimester. Odds ratio for future thyrotoxicosis was 3.64 in the lowest compared to the highest TSH quartile and 10.03 in those with TSH<0.1 compared to TSH 0.41-4 mU/l. Rates of female fetuses were higher in the low TSH quartiles and in the lower TSH groups, however baby gender was not associated with increased risk of future thyrotoxicosis. Low maternal 1(st) trimester TSH quartiles or concentrations were not associated with adverse pregnancy outcome. Only a minor fraction of pregnant women with a low first tirmester TSH subsequently developed future thyrotoxicosis.

Evolutionary origins of the placental expression of chromosome 19 cluster galectins and their complex dysregulation in preeclampsia.

INTRODUCTION: The dysregulation of maternal-fetal immune tolerance is one of the proposed mechanisms leading to preeclampsia. Galectins are key regulator proteins of the immune response in vertebrates and maternal-fetal immune tolerance in eutherian mammals. Previously we found that three genes in a Chr19 cluster encoding for human placental galectin-13 (PP13), galectin-14 and galectin-16 emerged during primate evolution and may confer immune tolerance to the semi-allogeneic fetus. MATERIALS AND METHODS: This study involved various methodologies for gene and protein expression profiling, genomic DNA methylation analyses, functional assays on differentiating trophoblasts including gene silencing, luciferase reporter and methylation assays. These methods were applied on placental specimens, umbilical cord blood cells, primary trophoblasts and BeWo cells. Genomic DNA sequences were analyzed for transposable elements, transcription factor binding sites and evolutionary conservation. RESULTS AND DISCUSSION: The villous trophoblastic expression of Chr19 cluster galectin genes is developmentally regulated by DNA methylation and induced by key transcription factors of villous placental development during trophoblast fusion and differentiation. This latter mechanism arose via the co-option of binding sites for these transcription factors through promoter evolution and the insertion of an anthropoid-specific L1PREC2 transposable element into the 5' untranslated region of an ancestral gene followed by gene duplication events. Among placental Chr19 cluster galectin genes, the expression of LGALS13 and LGALS14 is down-regulated in preterm severe preeclampsia associated with SGA. We reveal that this phenomenon is partly originated from the dysregulated expression of key transcription factors controlling trophoblastic functions and galectin gene expression. In addition, the differential DNA methylation of these genes was also observed in preterm preeclampsia irrespective of SGA. CONCLUSIONS: These findings reveal the evolutionary origins of the placental expression of Chr19 cluster galectins. The complex dysregulation of these genes in preeclampsia may alter immune tolerance mechanisms at the maternal-fetal interface.

Clinical significance of early (< 20 weeks) vs. late (20-24 weeks) detection of sonographic short cervix in asymptomatic women in the mid-trimester.

OBJECTIVE: The aim of this study was to determine whether the risk of early spontaneous preterm delivery (PTD) in asymptomatic women with a sonographic cervical length of ≤ 15 mm in the mid-trimester changes as a function of gestational age at diagnosis. METHODS: This cohort study included 109 asymptomatic patients with a sonographic cervical length of ≤ 15 mm diagnosed at 14-24 weeks of gestation. Women with a multifetal gestation, cerclage and a cervical dilatation of > 2 cm were excluded. The study population was stratified by gestational age at diagnosis (< 20 weeks vs. 20-24 weeks) and by cervical length (≤ 10 mm vs. 11-15 mm). The primary outcome variables were PTD at < 28 and < 32 weeks of gestation and the diagnosis-to-delivery interval. RESULTS: The median gestational age at diagnosis of a short cervix before 20 weeks and at 20-24 weeks was 18.9 and 22.7 weeks, respectively. Women diagnosed before 20 weeks had a higher rate of PTD at < 28 weeks (76.9% vs. 30.9%; P < 0.001) and at < 32 weeks (80.8% vs. 48.1%; P = 0.004), and a shorter median diagnosis-to-delivery interval (21 vs. 61.5 days, P = 0.003) than those diagnosed at 20-24 weeks. The rate of amniotic fluid sludge was higher among patients diagnosed with a short cervix at < 20 weeks of gestation than in those in whom it was diagnosed between 20 and 24 weeks (92.3% vs. 48.2%; P < 0.001). CONCLUSIONS: Asymptomatic women with a sonographic cervical length of ≤ 15 mm diagnosed before 20 weeks of gestation have a dramatic and significantly higher risk of early preterm delivery than women diagnosed at 20-24 weeks. These findings can be helpful to physicians in counseling these patients, and may suggest different mechanisms of disease leading to a sonographic short cervix before or after 20 weeks of gestation.

Plasma soluble endoglin concentration in pre-eclampsia is associated with an increased impedance to flow in the maternal and fetal circulations.

OBJECTIVES: To examine the relationship between abnormalities in uterine (UtA) and/or umbilical artery (UA) Doppler velocimetry and maternal plasma concentrations of soluble endoglin (sEng) in patients with pre-eclampsia (PE). METHODS: A cross-sectional study was conducted in 135 normal pregnant women and 69 patients with PE. Patients with PE were subclassified into four groups: those who had Doppler abnormalities in both the UtA and UA, patients who had Doppler abnormalities in the UtA alone, those who had Doppler abnormalities in the UA alone, and patients without Doppler abnormalities in either vessel. Plasma concentrations of sEng were determined by enzyme-linked immunosorbent assay. RESULTS: Among patients with PE, those with abnormal UtA and UA Doppler velocimetry had the highest median plasma concentration of sEng compared with any other group (P < 0.001, Kruskal-Wallis test). Women with PE with normal Doppler velocimetry in both vessels had the lowest median plasma concentration of sEng. There was a significant relationship between plasma concentrations of sEng and mean UtA resistance index (Spearman Rho = 0.5, P < 0.001) as well as UA pulsatility index (Spearman Rho = 0.4, P = 0.002). Multiple regression analysis suggested that Doppler abnormalities in the UtA and UA as well as gestational age at blood sampling contributed to plasma sEng concentrations (P < 0.001). CONCLUSIONS: Abnormalities of impedance to blood flow in the UtA and UA are associated with an excess of sEng in the circulation of mothers with PE. These findings suggest that the 'antiangiogenic state' in PE is partially reflected in abnormalities of Doppler velocimetry.

Expression patterns of microRNAs in the chorioamniotic membranes: a role for microRNAs in human pregnancy and parturition.

MicroRNAs (miRNAs) are involved in the post-transcriptional regulation of gene expression during development. This study was performed to determine gestational age-dependent changes in miRNA expression in the chorioamniotic membranes and to assess the significance of miRNAs in human pregnancy and parturition. The expression profile of 455 miRNAs was compared between patients at term without labour (TNL: n = 10), in labour (TL: n = 10), and preterm labour (PTL: n = 10) using microarrays. A total of 39 miRNAs were differentially expressed between term and preterm cases, of which 31 (79.5%) were down-regulated at term. Expression of ten miRNAs, including miR-338, differentially expressed between PTL and TL groups was decreased at term. Computational analyses using miRBase Targets have identified PLA2G4B, a phospholipase implicated in parturition, as a putative target of miR-338. Inhibition of endogenous miR-338 with anti-miR-338 increased the mRNA and protein expression of PLA2G4B in decidual cells. Luciferase assay with reporter constructs confirmed that the suppression of PLA2G4B occurs through binding of miR-338 to the 3UTR of PLA2G4B. Interestingly, the expression of Dicer, a key miRNA-processing enzyme, was markedly decreased at term, particularly with labour in the chorioamniotic membranes. Collectively, the novel findings reported herein strongly suggest that post-transcriptional regulation of genes by miRNAs, coupled with the changes of miRNA processing machinery in the chorioamniotic membranes, plays a role in pregnancy and parturition. Furthermore, the expression level of Dicer in the chorioamniotic membranes dichotomizes pathological preterm labour and physiological spontaneous labour at term.

Adiponectin multimers in maternal plasma.

OBJECTIVE: Adiponectin is an anti-diabetic, anti-atherogenic, anti-inflammatory, and angiogenic adipokine that circulates in oligomeric complexes including: low molecular weight (LMW) trimers, medium molecular weight (MMW) hexamers, and high molecular weight (HMW) isoforms. The aim of this study was to determine whether there are changes in adiponectin multimers in pregnancy and as a function of maternal weight. STUDY DESIGN: In this cross-sectional study, plasma concentrations of total, HMW, MMW, and LMW adiponectin were determined in women included in three groups: (1) normal pregnant women of normal body mass index (BMI) (n = 466), (2) overweight pregnant women (BMI >or=25; n = 257), and (3) non-pregnant women of normal weight (n = 40). Blood samples were collected once from each woman between 11 and 42 weeks of gestation. Plasma adiponectin multimer concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Non-parametric statistics were used for analysis. RESULTS: (1) The median HMW adiponectin concentration and the median HMW/total adiponectin ratio were significantly higher, and the median LMW adiponectin concentration was significantly lower in pregnant women than in non-pregnant women. (2) Among pregnant women, the median plasma concentration of total, HMW, and MMW adiponectin was significantly higher in normal weight women than in overweight patients. (3) Maternal HMW was the most prevalent adiponectin multimer regardless of gestational age or BMI status. (4) There were no significant differences in the median concentration of total, MMW, and LMW adiponectin and their relative distribution with advancing gestation. CONCLUSION: Human pregnancy is characterized by quantitative and qualitative changes in adiponectin multimers, especially the most active isoform, HMW adiponectin.

The use of inversion mode and 3D manual segmentation in volume measurement of fetal fluid-filled structures: comparison with Virtual Organ Computer-aided AnaLysis (VOCAL).

OBJECTIVE: Volume measurements by three-dimensional (3D) ultrasonography are considered more accurate than those performed by two-dimensional (2D) ultrasonography. The purpose of this study was to compare the agreement of three techniques, as well as the inter- and intraobserver agreements for volume measurements of fetal fluid-filled structures. METHODS: Fifty 3D volume datasets of fetal stomachs and bladders were explored. Volume measurements were performed independently by two observers using: (1) Virtual Organ Computer-aided AnaLysis (VOCAL); (2) inversion mode; and (3) 'manual segmentation'. Reliability was evaluated using intraclass correlation coefficient (ICC), and Bland-Altman plots were generated to examine bias and agreement. The time required to complete the measurements was compared using Student's t-test or the Wilcoxon Signed Rank Test, and P-values < 0.025 or < 0.05 were considered statistically significant. RESULTS: All volume datasets could be measured using the three techniques. A high degree of reliability was observed between: (1) VOCAL and inversion mode (ICC, 0.995; 95% CI, 0.992-0.997); (2) VOCAL and manual segmentation (ICC, 0.997; 95% CI, 0.995-0.998); and (3) inversion mode and manual segmentation (ICC, 0.995; 95% CI, 0.992-0.997). There was good agreement between VOCAL and inversion mode (mean, - 2.4%; 95% limits of agreement, - 20.1 to 15.3%), VOCAL and manual segmentation (mean, - 8.3%; 95% limits of agreement, - 28.8 to 12.2%) as well as between inversion mode and manual segmentation (mean, 5.9%, 95% limits of agreement: - 14.3 to 26%). Manual segmentation and inversion mode measurements were obtained significantly faster than those by VOCAL. CONCLUSIONS: Volume measurements of fetal fluid-filled structures of relatively regular shape with inversion mode and manual segmentation are feasible. Both techniques have good agreement with VOCAL and are significantly faster than VOCAL. Inversion mode is a reliable method for volume calculations of fluid-filled organs, whereas manual segmentation can be used when volume measurements by VOCAL or inversion mode are technically difficult to obtain, such as solid structures with poorly defined borders as the volume dataset is rotated, like the uterine cervix.

The effect of gestational age and labor on placental growth hormone in amniotic fluid.

OBJECTIVE: Placental growth hormone (PGH) is produced by trophoblast. This hormone becomes detectable in maternal serum during the first trimester of pregnancy. Its concentration increases as term approaches and becomes undetectable within one hour of delivery. PGH has important biological properties, including somatogenic (growth promotion), lactogenic, and lipolytic activity. Recently, PGH has been detected in amniotic fluid (AF) of midtrimester pregnancies. The purpose of this study was to determine whether PGH concentrations in AF change with advancing gestational age and in labor at term. DESIGN: AF was assayed for PGH concentrations in samples obtained from patients undergoing genetic amniocentesis between 14 and 18 weeks of gestation (n=67), normal patients at term not in labor (n=24), and pregnant women at term in labor (n=51). PGH concentrations were determined by ELISA. Non-parametric statistics were used for analysis. RESULTS: (1) PGH was detected in all AF samples; (2) patients in the midtrimester had a higher median concentration of PGH in AF than those at term (midtrimester: median: 3140.5 pg/ml; range: 1124.2-13886.5 vs. term: median: 2021.1pg/ml; range: 181.6-8640.8; p<0.01); (3) there was no difference in the median concentration of PGH between women at term, not in labor, and those in labor (term not in labor: median: 2113.4pg/ml; range: 449.3-8640.8 vs. term in labor: median: 2004.1pg/ml; range: 181.6-8531.5; p=0.73). CONCLUSIONS: (1) PGH is detectable in AF at both mid- and third trimesters; (2) the median AF concentration of PGH is significantly lower at term when compared to the second trimester; (3) labor at term is not associated with changes in the AF concentration of PGH. The role of this unique placental hormone now found in the fetal compartment requires further investigation.

Clinical significance of the presence of amniotic fluid 'sludge' in asymptomatic patients at high risk for spontaneous preterm delivery.

OBJECTIVES: To determine the clinical significance of the presence of amniotic fluid (AF) 'sludge' among asymptomatic patients at high risk for spontaneous preterm delivery. METHODS: This retrospective case-control study included 281 patients with (n = 66) or without (n = 215) AF 'sludge', who underwent transvaginal ultrasound examination between 13 and 29 completed weeks of gestation. Patients with threatened preterm labor, multiple gestation, fetal anomalies, placenta previa or uterine contractions were excluded. RESULTS: The prevalence of AF 'sludge' in the study population was 23.5% (66/281). The rates of spontaneous preterm delivery at < 28 weeks, < 32 weeks, < 35 weeks and < 37 weeks of gestation were 14.7% (29/197), 21.3% (46/216), 28.7% (62/216) and 42.1% (91/216), respectively. Patients with 'sludge' had: (1) a higher rate of spontaneous preterm delivery at < 28 weeks (46.5% (20/43) vs. 5.8% (9/154); P < 0.001), < 32 weeks (55.6% (25/45) vs. 12.3% (21/171); P < 0.001) and < 35 weeks (62.2% (28/45) vs. 19.9% (34/171); P < 0.001); (2) a higher frequency of clinical chorioamnionitis (15.2% (10/66) vs. 5.1% (11/215); P = 0.007), histologic chorioamnionitis (61.5% (40/65) vs. 28% (54/193); P < 0.001) and funisitis (32.3% (21/65) vs. 19.2% (37/193); P = 0.03); (3) a higher frequency of preterm prelabor rupture of membranes (PROM) (39.4% (26/66) vs. 13.5% (29/215); P < 0.001), lower gestational age at preterm PROM (median 24.7 (interquartile range (IQR), 22.3-28.1) weeks vs. 32.3 (IQR, 27.7-34.8) weeks; P < 0.001); and (4) shorter median ultrasound-to-delivery interval ('sludge' positive 127 days (95% CI, 120-134 days) vs. 'sludge' negative 161 days (95% CI, 153-169 days); P < 0.001) and ultrasound-to-preterm PROM interval ('sludge' positive 23 days (95% CI, 7-39 days) vs. 'sludge' negative 57 days (95% CI, 38-77 days); P = 0.003) than those without 'sludge'. AF 'sludge' was an independent explanatory variable for the occurrence of spontaneous preterm delivery at < 28 weeks, < 32 weeks and < 35 weeks, preterm PROM, microbial invasion of the amniotic cavity (MIAC) and histologic chorioamnionitis. Moreover, the combination of a cervical length < 25 mm and 'sludge' conferred an odds ratio of 14.8 and 9.9 for spontaneous preterm delivery at < 28 weeks and < 32 weeks, respectively. CONCLUSIONS: AF 'sludge' is an independent risk factor for spontaneous preterm delivery, preterm PROM, MIAC and histologic chorioamnionitis in asymptomatic patients at high risk for spontaneous preterm delivery. Furthermore, the combination of 'sludge' and a short cervix confers a higher risk for spontaneous preterm delivery at < 28 weeks and < 32 weeks than a short cervix alone.

Distribution of CD14+ and CD68+ macrophages in the placental bed and basal plate of women with preeclampsia and preterm labor.

OBJECTIVE: Macrophages play a key role in implantation, placentation and parturition. Yet, whether or not the number of macrophages at the fetomaternal interface (basal plate of the placenta and placental bed) is altered in women with preeclampsia is the subject of controversy. The purpose of this study was to compare the immunoreactivity and distribution patterns of CD14 and CD68 positive macrophages in both the basal plate and placental bed from preeclamptic and non-preeclamptic pregnancies. METHODS: A cross-sectional study was conducted. Paraffin embedded sections of placental tissues and placental bed biopsies were obtained from patients with early onset preeclampsia (n=10) and from those with preterm labor/delivery (n=10) without preeclampsia matched for gestational age. Double immunohistochemistry using antibodies to CD14 and CD68 was performed, and the density of double or single positive cells in the basal plate and placental bed was evaluated. Non-parametric statistics were used for analysis. RESULTS: 1) A unique subset of CD14-/CD68+ cells was identified. The cells in question were present at a higher level in the decidua than in the myometrial segment of the placental bed (p<0.01); 2) The density and proportion of CD14+/CD68+ cells (double positive cells) were significantly higher in the myometrial segment than in the basal plate (p=0.0003); and 3) There were no significant differences in the density and patterns of immunopositive macrophages in the basal plate, the decidua, and the myometrium between women with preeclampsia and those with preterm labor/delivery (p>0.05). CONCLUSION: The macrophages at the fetomaternal interface can be dichotomized by CD14 and CD68 immunoreactivity. A gradient of CD14+/CD68+ macrophages was demonstrated between the superficial myometrium and the basal plate regardless of the etiology of preterm birth (preeclampsia or spontaneous preterm labor). The biological function of single positive (CD14-/CD68+) and double positive (CD14+/CD68+) macrophages at the fetomaternal interface remains to be established. The overall findings also suggest that the discrepancies in the literature are due to the varying markers used to detect macrophages and in the anatomical plane of the fetomaternal junction analyzed.

Cervical length assessment in women with idiopathic polyhydramnios.

OBJECTIVE: The aims of the study were to determine cervical length among patients with polyhydramnios and to assess the relationship between the severity of polyhydramnios, cervical length and gestational age at delivery. PATIENTS AND METHODS: A prospective study was designed including 92 consecutive singleton pregnancies with polyhydramnios between 24 and 40 weeks' gestation. Cervical length was measured using transvaginal sonography. Polyhydramnios was defined when amniotic fluid index (AFI) was equal to or greater than 20 cm. A single sonologist performed all the examinations of the cervical length and the AFI. RESULTS: The median cervical length and AFI were 37.5 (range, 7-52) mm and 28.8 (range, 20-43) cm, respectively. A significant gradual shortening of the cervical length was observed with advancing gestational age (P=0.027). No significant association was found between AFI and cervical length (P=0.24). A cut-off of 15 mm (n=5) was associated with a significantly lower gestational age at delivery (30+/-2.6 weeks vs. 37.2+/-4.2 weeks, respectively, P<0.001). CONCLUSIONS: Women with polyhydramnios have a gradual shortening of cervical length with advancing gestational age. However, this finding is not related to the severity of polyhydramnios.

Overexpression of antizyme-inhibitor in NIH3T3 fibroblasts provides growth advantage through neutralization of antizyme functions.

Antizyme inhibitor (AzI) is a homolog of ornithine decarboxylase (ODC), a key enzyme of polyamine synthesis. Antizyme inhibitor retains no enzymatic activity, but exhibits high affinity to antizyme (Az), a negative regulator of polyamine homeostasis. As polyamines are involved in maintaining cellular proliferation, and since AzI may negate Az functions, we have investigated the role of AzI in regulating cell growth. We show here that overexpression of AzI in NIH3T3 cells increased growth rate, enabled growth in low serum, and permitted anchorage-independent growth in soft agar, while reduction of AzI levels by AzI siRNA reduced cellular proliferation. Moreover, AzI overproducing cells gave rise to tumors when injected into nude mice. AzI overexpression resulted in elevation of ODC activity and of polyamine uptake. These effects of AzI are a result of its ability to neutralize Az, as overexpression of an AzI mutant with reduced Az binding failed to alter cellular polyamine metabolism and growth properties. We also demonstrate upregulation of AzI in Ras transformed cells, suggesting its relevance to some naturally occurring transformations. Finally, increased uptake activity rendered AzI overproducing and Ras-transformed cells more sensitive to toxic polyamine analogs. Our results therefore imply that AzI has a central and meaningful role in modulation of polyamine homeostasis, and in regulating cellular proliferation and transformation properties.

The preterm parturition syndrome.

The implicit paradigm that has governed the study and clinical management of preterm labour is that term and preterm parturition are the same processes, except for the gestational age at which they occur. Indeed, both share a common pathway composed of uterine contractility, cervical dilatation and activation of the membranes/decidua. This review explores the concept that while term labour results from physiological activation of the components of the common pathway, preterm labour arises from pathological signalling and activation of one or more components of the common pathway of parturition. The term "great obstetrical syndromes" has been coined to reframe the concept of obstetrical disease. Such syndromes are characterised by: (1) multiple aetiology; (2) long preclinical stage; (3) frequent fetal involvement; (4) clinical manifestations that are often adaptive in nature; and (5) gene-environment interactions that may predispose to the syndromes. This article reviews the evidence indicating that the pathological processes implicated in the preterm parturition syndrome include: (1) intrauterine infection/inflammation; (2) uterine ischaemia; (3) uterine overdistension; (4) abnormal allograft reaction; (5) allergy; (6) cervical insufficiency; and (7) hormonal disorders (progesterone related and corticotrophin-releasing factor related). The implications of this conceptual framework for the prevention, diagnosis, and treatment of preterm labour are discussed.

The use of high-dimensional biology (genomics, transcriptomics, proteomics, and metabolomics) to understand the preterm parturition syndrome.

High-dimensional biology (HDB) refers to the simultaneous study of the genetic variants (DNA variation), transcription (messenger RNA [mRNA]), peptides and proteins, and metabolites of an organ, tissue, or an organism in health and disease. The fundamental premise is that the evolutionary complexity of biological systems renders them difficult to comprehensively understand using only a reductionist approach. Such complexity can become tractable with the use of "omics" research. This term refers to the study of entities in aggregate. The current nomenclature of "omics" sciences includes genomics for DNA variants, transcriptomics for mRNA, proteomics for proteins, and metabolomics for intermediate products of metabolism. Another discipline relevant to medicine is pharmacogenomics. The two major advances that have made HDB possible are technological breakthroughs that allow simultaneous examination of thousands of genes, transcripts, and proteins, etc., with high-throughput techniques and analytical tools to extract information. What is conventionally considered hypothesis-driven research and discovery-driven research (through "omic" methodologies) are complementary and synergistic. Here we review data which have been derived from: 1) genomics to examine predisposing factors for preterm birth; 2) transcriptomics to determine changes in mRNA in reproductive tissues associated with preterm labour and preterm prelabour rupture of membranes; 3) proteomics to identify differentially expressed proteins in amniotic fluid of women with preterm labour; and 4) metabolomics to identify the metabolic footprints of women with preterm labour likely to deliver preterm and those who will deliver at term. The complementary nature of discovery science and HDB is emphasised.

Mechanism of polyamine tolerance in yeast: novel regulators and insights.

Polyamines are small charged molecules essential for various cellular functions, but at high levels they are cytotoxic. Two yeast kinases, SKY1 and PTK2, have been demonstrated to regulate polyamine tolerance. Here we report the identification and characterization of additional genes involved in regulating polyamine tolerance: YGL007W, FES1 and AGP2. Deletion of YGL007W, an open reading frame located within the promoter of the membrane proton pump PMA1, decreased Pma1p expression. Deletion of FES1 or AGP2 resulted in reduced polyamine uptake. While high-affinity spermine uptake was practically absent in agp2Delta cells, fes1Delta cells displayed only reduced affinity towards spermine. Despite the reduced uptake, the resistant strains accumulated significant levels of polyamines and displayed increased ornithine decarboxylase activity, suggesting reduced polyamine sensing. Interestingly, fes1Delta cells were highly sensitive to salt ions, suggesting different underlying mechanisms. These results indicate that mechanisms leading to polyamine tolerance are complex, and involve components other than uptake.