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Offer Erez,1,2 Maha Othman,3 Anat Rabinovich,4 Elad Leron,5 Francesca Gotsch,6 Jecko Thachil7 1Maternity Department “D”, Division of Obstetrics and Gynecology, Soroka University Medical Center, School of Medicine, Faculty of Health Sciences Ben Gurion University of the Negev, Beer Sheva, Israel; 2Department of Obstetrics and Gynecology, Hutzel Women’s Hospital, Wayne State University, Detroit, MI, USA; 3Department of Biomedical and Molecular Sciences, School of Medicine, Queen’s University, Kingston, ON, Canada; 4Thrombosis and Hemostasis Unit, Hematology Institute, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; 5Division of Obstetrics and Gynecology, Soroka University Medical Center, School of Medicine, Faculty of Health Sciences Ben Gurion University of the Negev, Beer Sheva, Israel; 6Department of Obstetrics and Gynecology, Azienda Ospedaliera Universitaria Integrata, AOUI Verona, University of Verona, Verona, Italy; 7Department of Haematology, Manchester Royal Infirmary, Manchester, UKCorrespondence: Offer ErezMaternity Department “D” and Obstetrical Day Care Center, Division of Obstetrics and Gynecology, Soroka University Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, 84101, IsraelEmail erezof@bgu.ac.ilAbstract: Obstetrical hemorrhage and especially DIC (disseminated intravascular coagulation) is a leading cause for maternal mortality across the globe, often secondary to underlying maternal and/or fetal complications including placental abruption, amniotic fluid embolism, HELLP syndrome (hemolysis, elevated liver enzymes and low platelets), retained stillbirth and acute fatty liver of pregnancy. Various obstetrical disorders can present with DIC as a complication; thus, increased awareness is key to diagnosing the condition. DIC patients can present to clinicians who may not be experienced in a variety of aspects of thrombosis and hemostasis. Hence, DIC diagnosis is often only entertained when the patient already developed uncontrollable bleeding or multi-organ failure, all of which represent unsalvageable scenarios. Beyond the clinical presentations, the main issue with DIC diagnosis is in relation to coagulation test abnormalities. It is widely believed that in DIC, patients will have prolonged prothrombin time (PT) and partial thromboplastin time (PTT), thrombocytopenia, low fibrinogen, and raised D-dimers. Diagnosis of DIC can be elusive during pregnancy and requires vigilance and knowledge of the physiologic changes during pregnancy. It can be facilitated by using a pregnancy specific DIC score including three components: 1) fibrinogen concentrations; 2) the PT difference – relating to the difference in PT result between the patient’s plasma and the laboratory control; and 3) platelet count. At a cutoff of ≥ 26 points, the pregnancy specific DIC score has 88% sensitivity, 96% specificity, a positive likelihood ratio (LR) of 22, and a negative LR of 0.125. Management of DIC during pregnancy requires a prompt attention to the underlying condition leading to this complication, including the delivery of the patient, and correction of the hemostatic problem that can be guided by point of care testing adjusted for pregnancy.Keywords: DIC, hyperfibrinolysis, thrombin, pregnancy specific DIC score, maternal mortality, placental abruption

Offer Erez1, Lena Novack2, Vered Kleitman-Meir1, Doron Dukler1, Idit Erez-Weiss3, Francesca Gotsch4, Moshe Mazor11Department of Obstetrics and Gynecology, Soroka University Medical Center, 2Department of Epidemiology, 3Department of Family Medicine, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 4Obstetrics and Gynecology Departement, Policlinico GB Rossi Azienda Ospedaliera Universitaria Integrata Verona, ItalyPurpose: To determine the effects of vaginal birth after cesarean (VBAC) versus repeated cesarean sections (RCS) after a primary cesarean section (CS), on the rate of intraoperative and postpartum maternal morbidity.Patients and methods: This is a retrospective population-based cohort study. During the study period (1988–2005) there were 200,012 deliveries by 76,985 women at our medical center; 16,365 of them had a primary CS, of which 7429 women delivered a singleton infant after the primary CS, met the inclusion criteria, were included in our study, and were followed for four consecutive deliveries. Patients were divided into three study groups according to the outcome of their consecutive delivery after the primary CS: VBAC (n = 3622), elective CS (n = 1910), or an urgent CS (n = 1897). Survival analysis models were used to investigate the effect of the urgency of CS and the numbers of pregnancy predating the primary CS on peripartum complications.Results: Women who failed a trial of labor had a higher rate of uterine rupture than those who had a VBAC. Patients who delivered by CS had a higher rate of endometritis than those giving birth vaginally. The rate of cesarean hysterectomy and transfer to other departments increased significantly at the fourth consecutive surgery (P = 0.02 and P = 0.003, respectively). VBAC was associated with a 55% reduction in the risk of intrapartum complications in comparison to a planned CS (hazard ratio [HR] 0.45; 95% confidence interval [CI]: 0.22–0.89. A greater maternal parity at the time of primary CS was associated with lower intrapartum and postpartum morbidities (HR 0.44; 95% CI: 0.24–0.79; HR 0.54; 95% CI: 0.47–0.62, respectively).Conclusions: (1) A successful VBAC is associated with a reduction in the intrapartum complications; and (2) maternal morbidity increases substantially from the fourth consecutive cesarean delivery.Keywords: trial of labor, uterine rupture, hysterectomy, blood transfusion, parity

The article presents a cohort study that determine whether the risk of early spontaneous preterm delivery (PTD) in asymptomatic women with a sonographic cervical length of less than equal to 15 mm in the mid-trimester alters as a function of gestational age at diagnosis. It states that the study population comprise of 109 asymptomatic patients. The study finds that asymptomatic women have a dramatic and significantly higher risk of early preterm delivery than women diagnosed at 20-24 weeks.

Objective: Dysregulation of maternal circulating adipokines has been implicated in several 'great obstetrical syndromes' including preeclampsia (PE), small-for-gestational age (SGA) neonate and fetal death (FD). It has been suggested that adipokines provide a molecular link between metabolic derangements and inflammatory response in complicated pregnancies. Retinol binding protein 4 (RBP4), a novel adipokine, plays a role in obesity-related disorders, as well as in the regulation of the immune response. The aim of this study was to determine whether there are changes in maternal plasma concentrations of RBP4 in patients with PE and in those with an SGA neonate or FD. Study design: This cross-sectional study included patients in the following groups: 1) normal pregnancy (n=134); 2) PE (n=104); 3) SGA neonate (n=28); and 4) FD (n=37). Maternal plasma RBP4 concentrations were determined by ELISA. Non-parametric statistics were used for analysis. Results: 1) The median maternal plasma RBP4 concentration was higher among patients with PE than in those with a normal pregnancy (P=0.03); 2) The median maternal plasma RBP4 concentrations of patients with preterm PE (<37 weeks) was higher than that of those with term PE (P=0.017) and than that of those with a normal pregnancy (P=0.002); 3) The median maternal plasma RBP4 concentration did not differ significantly between patients with a normal pregnancy and those with an SGA neonate or with an FD; 4) Among normal pregnant women, the maternal plasma RBP4 concentrations did not correlate with pre-pregnancy body mass index, gestational age at blood sampling and neonatal birthweight. Conclusions: 1) Preeclampsia, but not pregnancy with an SGA neonate or an FD, is associated with a higher median maternal plasma concentration of RBP4 than normal pregnancy; 2) Preterm PE, and specifically early-onset PE, is associated with higher median RBP4 concentrations in maternal plasma compared to term PE. These findings suggest a role for RBP4 in the pathogenesis of preterm PE, but not in SGA and FD. [ABSTRACT FROM AUTHOR]

Objective: Intrauterine devices (IUDs) are used for contraception worldwide; however, the management of pregnancies with an IUD poses a clinical challenge. The purpose of this study was to determine the outcome of pregnancy in patients with an IUD. Study design: A retrospective cohort study (December 1997-June 2007) was conducted. The cohort consisted of 12,297 pregnancies, of which 196 had an IUD. Only singleton pregnancies were included. Logistic regression analysis was used to adjust for potential confounders between the groups. Results: 1) Pregnancies with an IUD were associated with a higher rate of late miscarriage, preterm delivery, vaginal bleeding, clinical chorioamnionitis, and placental abruption than those without an IUD; 2) among patients with available histologic examination of the placenta, the rate of histologic chorioamnionitis and/or funisitis was higher in patients with an IUD than in those without an IUD (54.2% vs. 14.7%; P<0.001). Similarly, among patients who underwent an amniocentesis, the prevalence of microbial invasion of the amniotic cavity (MIAC) was also higher in pregnant women with an IUD than in those without an IUD (45.9% vs. 8.8%; P<0.001); and 3) intra-amniotic infection caused by Candida species was more frequently present in pregnancies with an IUD than in those without an IUD (31.1% vs. 6.3%; P<0.001). Conclusion: Pregnant women with an IUD are at a very high risk for adverse pregnancy outcomes. This finding can be attributed, at least in part, to the high prevalence of intra-amniotic infection and placental inflammatory lesions observed in pregnancies with an IUD. [ABSTRACT FROM AUTHOR]

Objective: Adipose tissue dysfunction, characterized by dysregulation of adipokines production and/or secretion, has been implicated in the pathophysiology of type-2 diabetes mellitus, a metabolic complication closely related to gestational diabetes mellitus (GDM). Recently, an association between circulating maternal visfatin, a novel adipokine with metabolic and immunoregulatory properties, and impaired glucose metabolism as well as with altered fetal growth, has been proposed. The aims of this study were to determine whether there is an association between maternal plasma visfatin concentration, GDM, and a large-for-gestational-age (LGA) newborn. Study design: This cross-sectional study, included pregnant women at term in the following groups: 1) normal pregnancy and an appropriate-for-gestational-age (AGA) neonate (n=54); 2) normal pregnancy and an LGA newborn (n=47); 3) GDM and an AGA newborn (n=56); 4) GDM and an LGA newborn (n=45). The study population was further stratified by first trimester BMI (<25 vs. >=25 kg/m2). Maternal plasma visfatin concentration was determined by ELISA. Parametric and non-parametric statistics were used for analysis. Results: 1) Among women who delivered an AGA neonate, the median maternal plasma concentration of visfatin was higher in patients with GDM than in those with a normal pregnancy; 2) Among women with a normal pregnancy, those who delivered an LGA neonate had a higher median maternal plasma visfatin concentration than those who delivered an AGA neonate; 3) among patients with normal BMI, there were no significant differences in the median maternal plasma visfatin concentration between the four study groups; and 4) maternal GDM, as well as delivery of an LGA neonate were independently associated with a higher maternal plasma visfatin concentrations. Conclusion: The linkage between increased maternal circulating visfatin and the presence of GDM or delivery of an LGA neonate supports the hypothesis that perturbation of adipokines homeostasis may play a role in the pathophysiology of GDM or excess fetal growth. [ABSTRACT FROM AUTHOR]

Objective: Visfatin, a novel adipokine originally discovered as a pre-B-cell colony enhancing factor, is expressed by amniotic epithelium, cytotrophoblast, and decidua and is over-expressed when fetal membranes are exposed to mechanical stress and/or pro-inflammatory stimuli. Visfatin expression by fetal membranes is dramatically up-regulated after normal spontaneous labor. The aims of this study were to determine if visfatin is detectable in amniotic fluid (AF) and whether its concentration changes with gestational age, spontaneous labor, preterm prelabor rupture of membranes (preterm PROM) and in the presence of microbial invasion of the amniotic cavity (MIAC). Methods: In this cross-sectional study, visfatin concentration in AF was determined in patients in the following groups: 1) mid-trimester (n=75); 2) term not in labor (n=27); 3) term in spontaneous labor (n=51); 4) patients with preterm labor with intact membranes (PTL) without MIAC who delivered at term (n=35); 5) patients with PTL without MIAC who delivered preterm (n=52); 6) patients with PTL with MIAC (n=25); 7) women with preterm PROM without MIAC (n=26); and 8) women with preterm PROM with MIAC (n=26). Non-parametric statistics were used for analysis. Results: 1) The median AF concentration of visfatin was significantly higher in patients at term than in mid-trimester; 2) Among women with PTL who delivered preterm, the median visfatin concentration was significantly higher in patients with MIAC than those without MIAC; 3) Similarly, patients with PTL and MIAC had a higher median AF visfatin concentration than those with PTL who delivered at term; 4) Among women with preterm PROM, the median AF visfatin concentration was significantly higher in patients with MIAC than those without MIAC. Conclusions: 1) Visfatin is a physiologic constituent of AF; 2) The concentration of AF visfatin increases with advancing gestational age; 3) AF visfatin concentration is elevated in patients with MIAC, regardless of the membrane status, suggesting that visfatin participates in the host response against infection. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study was undertaken to determine whether premature labor is associated with changes in the maternal plasma concentration of soluble CD40 ligand (sCD40L), a marker of platelet activation. METHODS: A cross-sectional study included patients in the following groups: 1) non-pregnant (n=21); 2) normal pregnancy (n=71); 3) normal pregnancy at term with (n=67) and without labor (n=88); 4) preterm labor (PTL) with intact membranes (n=136) that was divided into the following sub-groups: 4a) PTL who delivered at term (n=49); 4b) PTL without intra-amniotic infection and/or inflammation (IAI) who delivered preterm (n=54); and 4c) PTL with IAI who delivered preterm (n=33). sCD40L concentrations were measured by ELISA. RESULTS: The median maternal plasma sCD40L concentration was higher in pregnant than non-pregnant women (P=0.017). Patients with PTL had a higher median maternal plasma sCD40L concentration than women with normal pregnancies, regardless of the presence or absence of IAI and gestational age at delivery (P<0.001 for all comparisons). IAI was not associated with a higher median maternal plasma concentration of sCD40L. CONCLUSIONS: Normal pregnancy is a state in which there is a physiologic increase of sCD40L. PTL was associated with an increased median maternal plasma sCD40L concentration that could not be accounted for by IAI. Thus, our findings suggest that platelet activation occurs during an episode of preterm labor. [ABSTRACT FROM AUTHOR]

Abstract Objective: The receptor for advanced glycation end products (RAGE) has been proposed to participate in the innate and adaptive immune responses. RAGE can induce production of pro-inflammatory cytokines and chemokines, as well as neutrophil chemotaxis in a manner that may be suppressed or stimulated by soluble, truncated forms of RAGE including the soluble form of RAGE (sRAGE) and endogenous secretory RAGE (esRAGE). The objective of this study was to determine whether intra-amniotic infection/inflammation (IAI) is associated with changes in the amniotic fluid concentration of sRAGE and esRAGE. Study design: Amniotic fluid (AF) was retrieved from patients in the following groups: 1) mid-trimester (14-18 weeks of gestation; n=68); 2) term not in labor (n=24); 3) term in labor (n=51); 4) preterm labor and intact membranes (n=124); and 5) preterm PROM (n=80). Intra-amniotic infection and inflammation were defined as the presence of a positive amniotic fluid culture for microorganisms and an AF interleukin-6 concentration >/=2.6 ng/mL, respectively. The AF concentration of sRAGE and esRAGE were determined using specific and sensitive ELISAs which measured total immunoreactive sRAGE and esRAGE, respectively. Patients were matched for gestational age at amniocentesis to compare the AF concentration of sRAGE and esRAGE in patients with and without IAI. Non-parametric statistics were used for analysis and a P<0.05 was considered significant. Results: 1) Patients at term not in labor had higher median AF concentrations of sRAGE and esRAGE than those in the mid-trimester (P<0.001 for both comparisons) and those at term in labor (P=0.03 and P=0.04, respectively); 2) patients with preterm labor and intact membranes with intra-amniotic infection/inflammation (IAI) had higher median AF concentrations of sRAGE and esRAGE than those without IAI (P=0.02 and P=0.005, respectively); 3) similarly, patients with preterm PROM with IAI had higher median AF concentrations of sRAGE and esRAGE than those without IAI (P=0.03 and P=0.02, respectively). Conclusion: Intra-amniotic infection/inflammation is associated with increased amniotic fluid concentrations of sRAGE and esRAGE. Changes in the amniotic fluid concentration of sRAGE and esRAGE may represent part of the immune response to intra-amniotic infection/inflammation. [ABSTRACT FROM AUTHOR]

AIM: CCL20, also known as MIP-3 alpha, is a chemokine that participates in chemotaxis of immature dendritic cells, effector/memory T-cells, and B-lymphocytes. The objectives of this study were to determine whether CCL20 can be detected in amniotic fluid (AF) and if AF concentration of this chemokine changes with advancing gestational age, parturition (term and preterm), and intra-amniotic infection/inflammation (IAI). METHODS: A cross-sectional study was conducted including the following groups: (1) mid-trimester of pregnancy (n=65); (2) term not in labor (TNL; n=22); (3) term in labor (TIL; n=47); (4) spontaneous preterm labor (PTL) who delivered at term (n=57); (5) spontaneous PTL without IAI who delivered preterm (n=71); and (6) spontaneous PTL with IAI (n=38). AF CCL20 concentrations were determined using ELISA. RESULTS: (1) The median AF CCL20 concentration in TNL was higher than that of mid-trimester patients; (2) Women in spontaneous labor at term had a higher median AF concentration of CCL20 than patients at term not in labor; (3) Patients with spontaneous PTL and IAI had a significantly higher median AF concentration of CCL20 than those without IAI who delivered preterm and those who delivered at term. Moreover, women with spontaneous PTL without IAI who delivered preterm had a significantly higher median AF concentration than those with PTL who subsequently delivered at term. CONCLUSIONS: (1) CCL20 is a physiologic constituent of AF and its concentration increases as term approaches; (2) spontaneous labor (term and preterm) in the absence of IAI is associated with increased bioavailability of AF CCL20 suggesting that an increase in CCL20 is part of the common pathway of human parturition; (3) patients with IAI had dramatic elevations in the AF CCL20 concentrations suggesting that this chemokine participates in the host response to infection or other stimuli associated with intra-amniotic infection. [ABSTRACT FROM AUTHOR]

Introduction: Accumulating evidence suggests that an imbalance between pro-angiogenic (i.e., vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)) and anti-angiogenic factors (i.e., soluble VEGF receptor-1 (sVEGFR-1, also referred to as sFlt1)) is involved in the pathophysiology of preeclampsia (PE). Endoglin is a protein that regulates the pro-angiogenic effects of transforming growth factor beta, and its soluble form has recently been implicated in the pathophysiology of PE. The objective of this study was to determine if changes in maternal plasma concentration of these angiogenic and anti-angiogenic factors differ prior to development of disease among patients with normal pregnancies and those destined to develop PE (preterm and term) or to deliver a small for gestational age (SGA) neonate.Methods: This longitudinal nested case-control study included 144 singleton pregnancies in the following groups: (1) patients with uncomplicated pregnancies who delivered appropriate for gestational age (AGA) neonates (n = 46); (2) patients who delivered an SGA neonate but did not develop PE (n = 56); and (3) patients who developed PE (n = 42). Longitudinal samples were collected at each prenatal visit, scheduled at 4-week intervals from the first or early second trimester until delivery. Plasma concentrations of soluble endoglin (s-Eng), sVEGFR-1, and PlGF were determined by specific and sensitive ELISA.Results: (1) Patients destined to deliver an SGA neonate had higher plasma concentrations of s-Eng throughout gestation than those with normal pregnancies; (2) patients destined to develop preterm PE and term PE had significantly higher concentrations of s-Eng than those with normal pregnancies at 23 and 30 weeks, respectively (for preterm PE: p < 0.036 and for term PE: p = 0.002); (3) patients destined to develop PE (term or preterm) and those who delivered an SGA neonate had lower plasma concentrations of PlGF than those with a normal pregnancy throughout gestation, and the maternal plasma concentration of this analyte became detectable later among patients with pregnancy complications, compared to normal pregnant women; (4) there were no significant differences in the plasma concentrations of sVEGFR-1 between patients destined to deliver an SGA neonate and those with normal pregnancies; (5) patients destined to develop preterm and term PE had a significantly higher plasma concentration of sVEGFR-1 at 26 and 29 weeks of gestation than controls (p = 0.009 and p = 0.0199, respectively); and (6) there was no significant difference in the increment of sVEGFR-1 between control patients and those who delivered an SGA neonate (p = 0.147 at 25 weeks and p = 0.8285 at 40 weeks).Conclusions: (1) Changes in the maternal plasma concentration of s-Eng, sVEGFR-1, and PlGF precede the clinical presentation of PE, but only changes in s-Eng and PlGF precede the delivery of an SGA neonate; and (2) differences in the profile of angiogenic and anti-angiogenic response to intrauterine insults may determine whether a patient will deliver an SGA neonate, develop PE, or both. [ABSTRACT FROM AUTHOR]