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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]

The article discusses the role of leptin and adiponectin in pregnancy complications. Topics discussed include adipokine family of proteins, structure of adiponectin multimers, and circulating leptin and adiponectin in normal pregnancy. Also featured are common metabolic complications including insulin resistance, obesity, and metabolic syndrome.

Objective. Maternal circulating visfatin concentrations are higher in patients with a small-for-gestational-age (SGA) neonate than in those who delivered an appropriate-for-gestational age (AGA) neonate or in those with pre-eclampsia. It has been proposed that enhanced transfer of visfatin from the foetal to maternal circulation may account for the high concentrations of maternal visfatin observed in patients with an SGA neonate. The aims of this study were: (1) to determine whether cord blood visfatin concentrations differ between normal neonates, SGA neonates and newborns of pre-eclamptic mothers; and (2) to assess the relationship between maternal and foetal circulating visfatin concentrations in patients with an SGA neonate and those with pre-eclampsia. Study design. This cross-sectional study included 88 pregnant women and their neonates, as well as 22 preterm neonates in the following groups: (1) 44 normal pregnant women at term and their AGA neonates; (2) 22 normotensive pregnant women and their SGA neonates; (3) 22 women with pre-eclampsia and their neonates; and (4) 22 preterm neonates delivered following spontaneous preterm labour without funisitis or histologic chorioamnionitis, matched for gestational age with infants of pre-eclamptic mothers. Maternal plasma and cord blood visfatin concentrations were determined by ELISA. Non-parametric statistics were used for analyses. Results. (1) The median visfatin concentration was lower in umbilical cord blood than in maternal circulation, in normal pregnancy, SGA and pre-eclampsia groups ( p < 0.001 for all comparisons); (2) the median cord blood visfatin concentrations did not differ significantly between term AGA or SGA neonates, infants of mothers with pre-eclampsia and their gestational-age-matched preterm AGA neonates; (3) maternal and cord blood visfatin concentrations correlated only in the normal term group ( r = 0.48, p = 0.04). Conclusion. Circulating visfatin concentrations are lower in the foetal than in the maternal circulation and did not significantly differ between the study groups. Thus, it is unlikely that the foetal circulation is the source of the high maternal visfatin concentrations reported in patients with an SGA neonate. [ABSTRACT FROM AUTHOR]

Objective: Infection has been implicated in the pathogenesis of preeclampsia, yet the association between microbial invasion of the amniotic cavity (MIAC) and preeclampsia has not been determined. The aim of this study was to determine the prevalence, and microbial diversity associated with MIAC, as well as the nature of the host response to MIAC in patients with preeclampsia. Method of study: Amniotic fluid (AF) from 62 subjects with preeclampsia, not in labor, was analyzed with both cultivation and molecular methods. Broad-range and group-specific PCR assays targeting small subunit ribosomal DNA, or other gene sequences, from bacteria, fungi and archaea were used. Results were correlated with measurements of host inflammatory response, including AF white blood cell count and AF concentrations of glucose, interleukin-6 (IL-6) and MMP-8. Results: 1) The rate of MIAC in preeclampsia was 1.6% (1/62) based on cultivation techniques, 8% (5/62) based on PCR, and 9.6% (6/62) based on the combined results of both methods; 2) among the six patients diagnosed with MIAC, three had a positive PCR for Sneathia/Leptotrichia spp.; and 3) patients with MIAC were more likely to have evidence of an inflammatory response in the amniotic cavity than those without MIAC, as determined by a higher median AF IL-6 [1.65 ng/mL interquartile range (IQR): 0.35–4.62 vs. 0.22 ng/mL IQR: 0.12–0.51; P=0.002). Conclusion: The prevalence of MIAC in preeclampsia is low, suggesting that intra-amniotic infection plays only a limited role in preeclampsia. However, the unexpectedly high number of positive AF specimens for Sneathia/Leptotrichia warrants further investigation. [ABSTRACT FROM AUTHOR]

Objective. An anti-angiogenic state has been implicated in the pathophysiology of preeclampsia, fetal growth restriction and fetal death. Vascular endothelial growth factor (VEGF), an indispensible angiogenic factor for embryonic and placental development exerts its angiogenic properties through the VEGF receptor (VEGFR)-2. A soluble form of this protein (sVEGFR-2) has been recently detected in maternal blood. The aim of this study was to determine if fetal death was associated with changes in the concentrations of sVEGFR-2 in maternal plasma and amniotic fluid. Study Design. Maternal plasma was obtained from patients with fetal death ( n = 59) and normal pregnant women ( n = 134). Amniotic fluid was collected from 36 patients with fetal death and the control group consisting of patients who had an amniocentesis and delivered at term ( n = 160). Patients with fetal death were classified according to the clinical circumstances into the following groups: (1) unexplained; (2) preeclampsia and/or placental abruption; (3) chromosomal and/or congenital anomalies. Plasma and amniotic fluid concentrations of sVEGFR-2 were determined by ELISA. Non-parametric statistics and logistic regression analysis were applied. Results. (1) Patients with a fetal death had a significantly lower median plasma concentration of sVEGFR-2 than normal pregnant women ( p < 0.001). The median plasma concentration of sVEGFR-2 in patients with unexplained fetal death and in those with preeclampsia/abruption, but not that of those with congenital anomalies, was lower than that of normal pregnant women ( p = 0.006, p < 0.001 and p = 0.2, respectively); (2) the association between plasma sVEGFR-2 concentrations and preterm unexplained fetal death remained significant after adjusting for potential confounders (OR: 3.2; 95% CI: 1.4–7.3 per each quartile decrease in plasma sVEGFR-2 concentrations); (3) each subgroup of fetal death had a higher median amniotic fluid concentration of sVEGFR-2 than the control group ( p < 0.001 for each); (4) the association between amniotic fluid sVEGFR-2 concentrations and preterm unexplained fetal death remained significant after adjusting for potential confounders (OR: 15.6; 95% CI: 1.5–164.2 per each quartile increase in amniotic fluid sVEGFR-2 concentrations); (5) among women with fetal death, there was no relationship between maternal plasma and amniotic fluid concentrations of sVEGFR-2 (Spearman Rho: 0.02; p = 0.9). Conclusion. Pregnancies with a fetal death, at the time of diagnosis, are characterized by a decrease in the maternal plasma concentration of sVEGFR-2, but an increase in the amniotic fluid concentration of this protein. Although a decrease in sVEGFR-2 concentration in maternal circulation depends upon the clinical circumstances of fetal death, an increase in sVEGFR-2 concentration in amniotic fluid seems to be a common feature of fetal death. It remains to be determined if the perturbation in sVEGFR-2 concentrations in maternal and fetal compartments observed herein preceded the death of a fetus. [ABSTRACT FROM AUTHOR]

Objective. Women with preeclampsia and those who delivered a small-for-gestational-age (SGA) neonate share several mechanisms of disease, including chronic uteroplacental ischemia and failure of physiologic transformation of the spiral arteries. However, the clinical manifestation of these obstetrical syndromes is remarkably different. It has been proposed that an altered maternal metabolic state, as well as a unique circulating cytokines milieu, predispose women to develop either preeclampsia or SGA. Compelling evidence suggests that adipose tissue orchestrates both metabolic pathways and immunological responses via the production of adipokines. Visfatin is a novel adipocytokine with metabolic and immunomodulating properties. The objective of this study was to determine whether preeclampsia and SGA are associated with alterations in maternal circulating visfatin concentrations. Methods. This cross-sectional study included pregnant women in the following groups: (1) normal pregnancy ( n = 158); (2) patients with preeclampsia ( n = 43) of which 32 had an AGA and 11 had an SGA neonate; (3) patients without preeclampsia who delivered an SGA neonate ( n = 55). Maternal plasma visfatin concentrations were measured by ELISA. Nonparametric tests and multiple linear regression analysis were used. Results. (1) Women who delivered an SGA neonate had a higher median maternal plasma visfatin concentration than those with a normal pregnancy (20.0 ng/ml, interquartile range: 17.2–24.6 vs. 15.2 ng/ml, 12.1–19.2, respectively; P < 0.001) and than those with preeclampsia (14.5 ng/ml, 12.5–18.7; P < 0.001); (2) the median maternal plasma visfatin concentration did not differ significantly between patients with preeclampsia and those with a normal pregnancy ( P = 0.8); (3) among patients with preeclampsia, there was no significant difference in the median maternal plasma visfatin concentration between those with or without an SGA neonate ( P = 0.5); (4) in a linear regression model, delivery of an SGA neonate and pregestational body mass index were independently associated with increased visfatin concentration after adjustment for confounding factors (maternal age, smoking, gestational age at blood collection and the presence of preeclampsia or SGA). Conclusion. (1) Patients with SGA, but not those with preeclampsia, had a higher maternal plasma visfatin concentration than those with a normal pregnancy; (2) this finding suggests differential involvement of visfatin in SGA and preeclampsia; (3) we propose that changes in circulating maternal visfatin concentration may be implicated in the phenotypic definitions and distinction of preeclampsia and SGA. [ABSTRACT FROM AUTHOR]

Objective. Angiogenesis is critical for successful pregnancy. An anti-angiogenic state has been implicated in preeclampsia, fetal growth restriction and fetal death. Increased maternal plasma concentrations of the anti-angiogenic factor, soluble vascular endothelial growth factor receptor (sVEGFR)-1, have been reported in women with preeclampsia and in those with fetal death. Recent observations indicate that an excess of sVEGFR-1 and soluble endoglin (sEng) is also present in the amniotic fluid of patients with preeclampsia. The aim of this study was to determine whether fetal death is associated with changes in amniotic fluid concentrations of sVEGFR-1 and sEng, two powerful anti-angiogenic factors. Study design. This cross-sectional study included patients with fetal death ( n = 35) and controls ( n = 129). Fetal death was subdivided according to clinical circumstances into: (1) unexplained ( n = 25); (2) preeclampsia and/or placental abruption ( n = 5); and (3) chromosomal/congenital anomalies ( n = 5). The control group consisted of patients with preterm labor (PTL) who delivered at term ( n = 92) and women at term not in labor ( n = 37). AF concentrations of sVEGFR-1 and sEng were determined by ELISA. Non-parametric statistics and logistic regression analysis were applied. Results. (1) Patients with a fetal death had higher median amniotic fluid concentrations of sVEGFR-1 and sEng than women in the control group ( p < 0.001 for each); (2) these results remained significant among different subgroups of stillbirth ( p < 0.05 for each); and (3) amniotic fluid concentrations of sVEGFR-1 and those of sEng above the third quartile were associated with a significant risk of unexplained preterm fetal death (adjusted OR = 10.8; 95%CI 1.3–89.2 and adjusted OR 87; 95% CI 2.3–3323, respectively). Conclusion. Patients with an unexplained fetal death at diagnosis are characterized by an increase in the amniotic fluid concentrations of sVEGFR-1 and sEng. These observations indicate that an excess of anti-angiogenic factors in the amniotic cavity is associated with unexplained fetal death especially in preterm gestations. [ABSTRACT FROM AUTHOR]

Objective. The importance of an anti-angiogenic state as a mechanism of disease in preeclampsia is now recognized. Assays for the determination of concentrations of soluble vascular endothelial growth factor receptor (sVEGFR)-1, sVEGFR-2, placental growth factor (PlGF) and soluble endoglin (sEng) have been developed for research and clinical laboratories. A key question is whether these factors should be measured in plasma or serum. The purpose of this study was to determine if there are differences in the concentrations of these analytes between plasma and serum in normal pregnancy and in preeclampsia. Methods. Samples of maternal blood were obtained by venipuncture and collected in EDTA (lavender top) and serum collection tubes (red top). A standard laboratory procedure was implemented for the centrifugation, aliquoting and storage of samples. Plasma and serum from 70 women with normal pregnancies and 34 patients with preeclampsia were assayed for sVEGFR-1, sVEGFR-2, PlGF and sEng by ELISA. Nonparametric paired tests were used for analyses. Results. A significant difference between plasma and serum concentration was observed for sVEGFR-1 and sVEGFR-2 in normal pregnancy, and for sVEGFR-1, sVEGFR-2, PlGF and sEng in women with preeclampsia. Conclusion. The concentrations of sVEGFR-1, sVEGFR-2, PlGF and sEng when measured in maternal plasma and in serum are different. Therefore, the matrix used for the assay (serum versus plasma) needs to be considered when selecting thresholds for predictive studies and interpreting the growing body of literature on this subject. [ABSTRACT FROM AUTHOR]

Objective: Adipokines have been implicated in metabolic regulation and the immune response thus providing a molecular mechanism for the interaction between these two systems. Retinol binding protein 4 (RBP4) is a novel adipokine that plays a role in the pathophysiology of obesity-induced insulin resistance, as well as in the modulation of inflammation. The aim of this study was to determine whether there are changes in maternal plasma concentrations of RBP4 in pregnant women with acute pyelonephritis. Study design: This cross-sectional study included pregnant women in the following groups: 1) normal pregnancy (n=80); 2) pyelonephritis (n=39). Maternal plasma RBP4 concentrations were determined by enzyme-linked immunoassays. Non-parametric statistics were used for analyses. Results: 1) The median maternal plasma RBP4 concentration was lower in patients with acute pyelonephritis than in those with a normal pregnancy (3709.6 ng/mL, interquartile range (IQR) 2917.7–5484.2 vs. 9167.6 ng/mL, IQR 7496.1– 10,384.1, P<0.001; 2) the median maternal plasma RBP4 concentration did not differ significantly between patients with acute pyelonephritis who had a positive blood culture and those with a negative culture (3285.3 ng/mL, IQR 2274.1–4741.1 vs. 3922.6 ng/mL, IQR 3126.8–5547.1, respectively, P=0.2); and 3) lower maternal plasma RBP4 concentrations were independently associated with pyelonephritis after adjustment for confounding factors. Conclusions: In contrast to what has been reported in preeclampsia, acute pyelonephritis during pregnancy is associated with lower maternal plasma RBP4 concentrations than in normal pregnancy. This finding suggests that the acute maternal inflammatory process associated with pyelonephritis is fundamentally different from that of the chronic systemic inflammatory process suggested in preeclampsia, in which RBP4 concentrations were found to be elevated. [ABSTRACT FROM AUTHOR]

Objective. Preeclampsia and pregnancies complicated by small-for-gestational age (SGA) neonates share several underlying mechanisms of disease. However, while an exaggerated systemic maternal inflammatory response is regarded as one of the hallmarks of the pathogenesis of preeclampsia, the presence of a similar systemic intra-vascular inflammation in mothers of SGA neonates without hypertension is controversial. The aim of this study was to determine phenotypic and metabolic changes in granulocytes and monocytes of women who develop preeclampsia and those who deliver an SGA neonate, compared to normal pregnant women. Methods. This cross-sectional study included patients with a normal pregnancy ( n = 33), preeclampsia ( n = 33), and an SGA without preeclampsia ( n = 33), matched for gestational age at blood sample collection. Granulocyte and monocyte phenotypes were determined by flow cytometry, using monoclonal antibodies against selective cluster of differentiation (CD) antigens. The panel of antibodies included the following: CD11b, CD14, CD16, CD18, CD49d, CD62L, CD64, CD66b, and HLA-DR. Intracellular reactive oxygen species (iROS) were assessed at the basal state and after stimulation (oxidative burst). Results were reported as mean channel brightness (MCB) or intensity of detected fluorescence. Analysis was conducted with non-parametric statistics. A p-value < 0.01 was considered statistically significant. Results. (1) Women who delivered an SGA neonate had a higher MCB of CD11b in granulocytes and monocytes than those with a normal pregnancy ( p < 0.001 for both); (2) patients with preeclampsia had a lower median MCB of CD62L in granulocytes ( p = 0.006) and a higher median basal iROS and oxidative burst in monocytes than women with an SGA neonate ( p = 0.003 and p = 0.002, respectively). Conclusion. Pregnancies complicated by the delivery of an SGA neonate are characterized by a higher activation of maternal peripheral leukocytes than in normal pregnancies, but lower than in pregnancies complicated by preeclampsia. [ABSTRACT FROM AUTHOR]

Objective: Idiopathic vaginal bleeding, a common complication of pregnancy, increases the risk of small-for-gestational age (SGA) neonate, preeclampsia and preterm delivery and can be the only clinical manifestation of intra-amniotic infection and/or inflammation (IAI). Placenta previa is thought to be protective against ascending intrauterine infection, yet an excess of histologic chorioamnionitis has been reported in this condition. The aim of this study was to determine the frequency and clinical significance of IAI in women with placenta previa and vaginal bleeding in the absence of preterm labor. Study design: A retrospective cohort study including 35 women with placenta previa and vaginal bleeding <37 weeks of gestation who underwent amniocentesis was undertaken. Patients with multiple gestations were excluded. Intra-amniotic infection was defined as a positive culture for microorganisms, and intra-amniotic inflammation as an elevated amniotic fluid interleukin (IL)-6 concentration. IL-6 concentrations were determined by ELISA in 28 amniotic fluid samples available. Non-parametric statistics were used for analysis. Results: 1) The prevalence of intra-amniotic infection was 5.7% (2/35), and that of IAI was 17.9% (5/28); 2) the gestational age at delivery was lower in patients with IAI than in those without IAI [29.4 weeks, interquartile range (IQR): 23.1–34.7 vs. 35.4 weeks, IQR: 33.9–36.9; P=0.028]; and 3) patients with placenta previa and IAI had a higher rate of delivery within 48 h (80% (4/5) vs. 19% (4/21); P=0.008) than those without IAI. Conclusions: Patients with placenta previa presenting with vaginal bleeding have intra-amniotic infection in 5.7% of the cases, and IAI in 17.9%. IAI in patients with placenta previa and vaginal bleeding is a risk factor for preterm delivery within 48 h. [ABSTRACT FROM AUTHOR]

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. Angiogenic factors have been implicated in the pathophysiology of sepsis. In experimental models of sepsis (endotoxemia and/or cecal ligation puncture), there is increased expression of vascular endothelial growth factors (VEGF) and the administration of exogenous soluble VEGF receptor (sVEGFR)-1, an antagonist to VEGF, reduces morbidity and mortality. Moreover, a dramatic elevation in sVEGFR-1 has been demonstrated in human sepsis. Although a balance between angiogenic and anti-angiogenic factors is essential for feto-placental development, the changes of angiogenic factors during pregnancy in the context of infection have never been explored. Angiogenic factors also play crucial roles in the pathophysiology of preeclampsia (PE). This study was conducted to determine if maternal plasma concentrations of placental growth factor (PlGF), sVEGFR-2, and soluble endoglin (sEng) change in pregnancies complicated by acute pyelonephritis (AP) compared with normal pregnancy and PE. Study design. A case-control study was conducted in patients with AP, normal pregnant (NP) women, and patients with PE ( n = 36 for each group) matched for gestational age. AP was diagnosed in the presence of fever (temperature ≥38°C), clinical signs of infection, and a positive urine culture for microorganisms. Plasma concentrations of PlGF, sVEGFR-2, and sEng were determined by ELISA. The results of plasma sVEGFR-1 concentrations have previously been reported, but were included in this study to provide a complete picture of the angiogenic/anti-angiogenic profiles. Serum concentrations of interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, interferon (IFN)-γ, granulocyte macrophage colony stimulating factor, and tumor necrosis factor (TNF) were also determined using high sensitivity multiplexed immunoassays in patients with AP and NP. Results. AP was associated with a lower median plasma concentration of PlGF and sVEGFR-2 than NP (both p < 0.001). There were no significant differences in the median plasma concentrations of sEng and sVEGFR-1 between AP and NP ( p = 0.7 and 0.5, respectively). In contrast, there was a 5-fold decrease of the median plasma concentration of PlGF, and an 8–10-fold increase of the median plasma concentrations of sVEGFR-1 and sEng in PE compared with those in AP (all p < 0.001). No significant difference in the median plasma concentration of sVEGFR-2 was observed between patients with PE and AP ( p = 0.5). Pregnant women with AP had median plasma concentrations of IL-6, IL-7, IL-8, IL-10, IFN-γ, and TNF-α significantly higher than those in NP women (all p < 0.001, except IL-7 p = 0.004). Conclusion. AP is associated with changes in the profile of angiogenic and anti-angiogenic factors. Although some of these changes resemble those in PE (decreased PlGF and sVEGFR-2), the magnitude of the changes of PlGF is much higher in PE. We conclude that despite high plasma inflammatory cytokine concentrations, acute systemic inflammation in pregnancy has a different angiogenic/anti-angiogenic profile than that of PE. [ABSTRACT FROM AUTHOR]

Objective. An imbalance between angiogenic and anti-angiogenic factors in maternal blood has been observed in several obstetrical syndromes including preeclampsia, pregnancies with fetal growth restriction and fetal death. Vascular lesions have been identified in a subset of patients with spontaneous preterm labor (PTL). It is possible that PTL may be one of the manifestations of an anti-angiogenic state. The aim of this study was to determine if patients prior to the clinical diagnosis of PTL leading to preterm delivery had plasma concentrations of angiogenic and anti-angiogenic factors different from normal pregnant women. Study Design. This longitudinal nested case–control study included normal pregnant women ( n = 208) and patients with PTL leading to preterm delivery ( n = 52). Maternal blood samples were collected at 6 gestational age intervals from 6 to36.9 weeks of gestation. The end point (time of diagnosis) of the study, ‘True PTL’, was defined as patients presenting with PTL and delivered within 1 day. Plasma concentrations of sVEGFR-1, sVEGFR-2, sEng and PlGF were determined by ELISA. Analysis was performed with both cross-sectional and longitudinal (mixed effects model) approaches. Results. (1) Plasma sEng concentration in patients destined to develop PTL was higher than that in normal pregnant women from 15–20 weeks of gestation. The difference became statistical significant at 28 weeks of gestation, or approximately 5–10 weeks prior to the diagnosis of ‘true PTL’. (2) Backward analysis suggests that plasma concentrations of PlGF and sVEGFR-2 were lower, and those of sVEGFR-1 were higher in patients with PTL than in normal pregnant women less than 5 weeks prior to the diagnosis of ‘true PTL’; and (3) Plasma concentrations of sEng and sVEGFR-1 were higher and those of PlGF and sVEGFR-2 were lower in patients diagnosed with PTL and delivery within 1 day than in normal pregnant women who delivered at term. Conclusion. The changes in sEng are demonstrable several weeks prior to the onset of preterm parturition. In contrast, the changes in the other angiogenic proteins are present close to the onset of PTL and delivery. This observation supports the view that an imbalance of angiogenic factors participates in the pathophysiology of spontaneous preterm parturition. [ABSTRACT FROM AUTHOR]

Objective. Changes in the maternal plasma concentrations of angiogenic (placental growth factor (PlGF) and vascular endothelial growth factor (VEGF)) and anti-angiogenic factors (sEng and vascular endothelial growth factor receptor-1 (sVEGFR-1)) precede the clinical presentation of preeclampsia. This study was conducted to examine the role of maternal plasma PlGF, sEng, and sVEGFR-1 concentrations in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia. Methods. This longitudinal cohort study included 1622 consecutive singleton pregnant women. Plasma samples were obtained in early pregnancy (6-15 weeks) and midtrimester (20-25 weeks). Maternal plasma PlGF, sEng, and sVEGFR-1 concentrations were determined using sensitive and specific immunoassays. The primary outcome was the development of preeclampsia. Secondary outcomes included term, preterm, and early-onset preeclampsia. Receiving operating characteristic curves, sensitivity, specificity, positive and negative likelihood ratios, and multivariable logistic regression were applied. A p-value of <0.05 was considered significant. Results. (1) The prevalence of preeclampsia, term, preterm, (<37 weeks) and early-onset preeclampsia (<34 weeks) was 3.8 (62/1622), 2.5 (40/1622), 1.4 (22/1622) and 0.6% (9/1622), respectively; (2) Higher likelihood ratios were provided by ratios of midtrimester plasma concentrations of PlGF, sEng, and sVEGFR-1 than single analytes; (3) Individual angiogenic and anti-angiogenic factors did not perform well in the identification of preeclampsia as a whole; in particular, they perform poorly in the prediction of term preeclampsia; (4) In contrast, a combination of these analytes such as the PlGF/sEng ratio, its delta and slope had the best predictive performance with a sensitivity of 100%, a specificity of 98-99%, and likelihood ratios for a positive test of 57.6, 55.6 and 89.6, respectively, for predicting early-onset preeclampsia. Conclusions. (1) The PlGF/sEng ratio and its delta and slope had an excellent predictive performance for the prediction of early-onset preeclampsia, with very high likelihood ratios for a positive test result and very low likelihood ratios for a negative test result; and (2) Although the positive likelihood ratios are high and the positive predictive values low, the number of patients needed to be closely followed is 4:1 for the PlGF/sEng ratio and 3:1 for the slope of PlGF/sEng. [ABSTRACT FROM AUTHOR]

Objective. Low maternal plasma protein Z (PZ) concentrations were reported in patients with pre-eclampsia (PE), a small for gestational age (SGA) neonate, and a fetal demise (FD). Anti-protein Z antibodies (APZ-AB) have been proposed as a possible underlying mechanism leading to low plasma PZ concentrations. The objective of this study was to determine the maternal plasma concentration of APZ-AB in women with a normal pregnancy, and patients with PE, an SGA neonate or a FD. Study design. A cross-sectional study included women in the following groups: (1) non-pregnant women (n = 45); and pregnant women with: (2) normal pregnancies (n = 70); (3) PE (n = 123); (4) SGA neonates (n = 51); and (5) a FD (n = 51). Plasma concentrations of anti-protein Z IgM and IgG antibodies were measured by ELISA. Elevated APZ-AB was defined as >75th, 90th and 95th percentile of the normal pregnancy group. Non-parametric statistics were used for analyses. Results. (1) Patients with an SGA neonate had a higher median maternal plasma IgG APZ-AB concentration than women with normal pregnancies (p < 0.001), and patients with PE (p < 0.001) or with a FD (p = 0.001). (2) The proportion of patients with a maternal plasma IgM APZ-AB concentration >90th percentile was higher in the SGA group than in the PE group (p = 0.01). (3) Patients with PE maternal plasma IgM APZ-AB concentration >90th percentile had a higher rate of villous thrombosis (p = 0.03) and persistent muscularisation of basal plate arteries (p = 0.01) than those with IgM APZ-AB concentration <90th percentile; and (5) Patients with FD and maternal plasma IgM APZ-AB concentration >90th percentile had a higher rate of umbilical phlebitis and arteritis than those with IgM APZ-AB concentration <90th percentile (p = 0.003). Conclusions. (1) Patients with SGA neonates have a higher median plasma concentration of IgG APZ-AB than normal pregnant women, or patients with PE or FD; and (2) maternal plasma IgM APZ-AB concentration >90th percentile was associated with vascular placental lesions in patients with PE, but not in those with an SGA neonate, suggesting that in a subset of patients, these antibodies can be associated with abnormal placentation and pregnancy complications. [ABSTRACT FROM AUTHOR]

Objective. Fetal death can lead to disseminated intravascular coagulation or fetal death syndrome. However, currently it is not clear what are the changes in the coagulation system in patients with a fetal death without the fetal death syndrome. This study was undertaken to determine: (1) whether fetal death in the absence of fetal death syndrome is associated with changes in hemostatic markers in maternal plasma and amniotic fluid; and (2) whether maternal hypertension or placental abruption are associated with further changes in the hemostatic profile of these patients. Methods. A cross-sectional study included the following: (1) determination of changes in markers of coagulation and platelet activation in patients with a normal pregnancy (n = 71) and patients with fetal demise (FD) without disseminated intravascular coagulation (n = 65); (2) determination of the amniotic fluid (AF)-tissue factor concentration and activity, as well as the concentrations of thrombin-antithrombin III (TAT) complexes in patients with a normal pregnancy (n = 25) and those with a FD (n = 36) who underwent amniocentesis. Plasma and AF concentrations of TAT complexes and TF (an index of thrombin generation), as well as maternal plasma concentrations of sCD40L (a marker of platelet activation), tissue factor pathway inhibitor (TFPI) and prothrombin fragments (PF) 1 + 2 (also an indicator of in vivo thrombin generation) were measured by ELISA. TF and TFPI activity were measured using chromogenic assays. Results. (1) patients with FD without hypertension had a higher median maternal plasma sCD40L concentration than normal pregnant women (P < 0.001); (2) patients with FD had a higher median maternal plasma TAT III complexes than women with a normal pregnancy (P < 0.001); (3) the median AF-TF concentration and activity were higher in the FD group than in the normal pregnancy group (P < 0.001 for both); (4) patients with preeclampsia and FD had a higher median maternal plasma immunoreactive TF concentration than both normotensive patients with FD and women with normal pregnancies (P < 0.001 and P = 0.001, respectively); (5) the median plasma TF activity was higher in patients with preeclampsia and FD than that of women with normal pregnancies (P = 0.003); (6) among patients with a FD, those with placental abruption had a higher median AF-TAT complexes concentration than those without abruption (P = 0.0004). Conclusions. Our findings indicate that: (1) mothers with a FD have evidence of increased in vivo thrombin generation and platelet activation than women with normal pregnancies; (2) patients with a FD and hypertension had a higher degree of TF activation than those with fetal death but without hypertension; (3) the AF of women with a FD had a higher median TF concentration and activity than that of normal pregnant women. AF can be a potential source for tissue factor and it participates in the development of fetal death syndrome in patients with a retained dead fetus. [ABSTRACT FROM AUTHOR]

Objective: Obesity, insulin resistance, and dyslipidemia are associated with preeclampsia. Recently, “adipose tissue failure”, characterized by dysregulation of adipokine production, has been implicated in the pathophysiology of these metabolic complications. Adiponectin, an insulin-sensitizing, anti-atherogenic, anti-inflammatory and angiogenic adipokine, circulates in oligomeric complexes including: low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. These multimers exert differential biological effects, and HMW to total adiponectin ratio (SA) has been reported to be a specific marker of adiponectin activity. The aim of this study was to determine whether preeclampsia is associated with changes in circulating adiponectin multimers. Study design: This cross-sectional study included women with: 1) normal pregnancy (n=225); and 2) patients with mild preeclampsia (n=111). The study population was further stratified by first trimester BMI (normal weight <25 kg/m2 vs. overweight/obese ≥25 kg/m2). Serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Non-parametric statistics were used for analysis. Results: 1) The median maternal HMW and LMW adiponectin concentrations were lower in patients with preeclampsia than in those with normal pregnancies (P<0.001 and P=0.01, respectively); 2) patients with preeclampsia had a lower HMW/total adiponectin ratio (P<0.001) and higher MMW/total adiponectin and LMW/total adiponectin ratios than those with a normal pregnancy (P<0.001 and P=0.009, respectively); 3) the presence of preeclampsia was independently associated with lower maternal serum HMW adiponectin concentrations (P=0.001) and with a low HMW/total adiponectin ratio (P<0.001) after correction for maternal age, maternal BMI, the difference in BMI between the third and the first trimester, and gestational age at sampling; and 4) overweight/obese pregnant women had a lower median total and HMW adiponectin concentration than normal weight pregnant women among women with normal pregnancies, but not among those with preeclampsia. Conclusion: 1) Preeclampsia is associated with a lower median concentration of the HMW adiponectin isoform, the most active form of this adipokine, and a low HMW/total adiponectin ratio, a specific marker of adiponectin biologic activity; 2) in contrast to normal pregnancy, preeclampsia is not associated with decreased circulating adiponectin multimers in overweight/obese individuals suggesting altered regulation of this adipokine in preeclampsia; 3) collectively, these findings suggest that preeclampsia is characterized by alterations in adiponectin multimers and their relative distribution implying a role for adiponectin multimers in the mechanism of disease in preeclampsia. [ABSTRACT FROM AUTHOR]

Objective. Tissue factor (TF), the major activator of the extrinsic pathway of coagulation, is abundant in the placenta and decidua. The aim of this study was to determine the maternal plasma concentrations of TF and its primary inhibitor, tissue factor pathway inhibitor (TFPI), in women who delivered small for gestational age (SGA) neonates, and in pre-eclampsia. Study design. A cross-sectional study included the following groups: 1) women with normal pregnancies (n = 86); 2) patients who delivered SGA neonates (n = 61) and 3) women with pre-eclampsia (n = 133). Maternal plasma concentrations of TF and TFPI were measured by a sensitive immunoassay. Non-parametric statistics were used for analysis. Results. 1) Women with pre-eclampsia had a significantly higher median plasma concentration of TF than patients with a normal pregnancy (median: 1187 pg/mL; range: 69-11675 vs. median: 291.5 pg/mL; range: 6.3-2662.2; p < 0.0001, respectively); 2) Similarly, TFPI concentrations were higher in pre-eclampsia than in normal pregnancy (median: 87.5ng/mL; range 25.4-165.1 vs. median: 66.1 ng/mL; range: 14.3-86.5; p < 0.0001, respectively); 3) Surprisingly, mothers with SGA neonates had a lower median maternal plasma concentration of TF (median: 112.2 pg/mL; range: 25.6-1225.3) than women with a normal pregnancy (p < 0.0001). Conclusion. 1) Maternal plasma concentrations of TF in patients with pre-eclampsia, but not in those who delivered an SGA neonate, were higher than in women with normal pregnancies; 2) Although the role of immunoreactive plasma TF in coagulation remains controversial, our observations suggest that changes are present in the context of complications of pregnancy. [ABSTRACT FROM AUTHOR]

Problem Mannose-binding lectin (MBL) is a pattern-recognition receptor that activates complement and modulates inflammation. Homozygosity for the most common allele of the MBL2 gene that is associated with high MBL serum concentrations is more prevalent among patients with pre-eclampsia. The objective of this study was to determine maternal plasma MBL concentrations in normal pregnant women and patients with pre-eclampsia. Method of study This cross-sectional study included normal pregnant women ( n = 187) and patients with pre-eclampsia ( n = 99). Maternal plasma MBL concentrations were determined by ELISA. Results Women with pre-eclampsia had a higher median maternal plasma MBL concentration than normal pregnant women. MBL concentration distribution curves were three-modal, the subintervals in normal pregnancy were low (<143.7), intermediate (143.7–1898.9) and high (>1898.9 ng/mL). The proportion of normal pregnant women was larger in the low subinterval, while the proportion of patients with pre-eclampsia was larger in the high subinterval ( P = 0.02). Normal pregnant women in the high subinterval had a larger rate of placental underperfusion than those in the low and intermediate subintervals ( P = 0.02). Conclusions The median maternal plasma MBL concentration is elevated in patients with pre-eclampsia and a larger proportion of these patients are in the high subinterval than normal pregnant women, suggesting that this component of the innate immune system is involved in the mechanisms of disease in pre-eclampsia. [ABSTRACT FROM AUTHOR]

Abstract: Hydatidiform mole with co-existing live fetus is a rare entity. Two cases are reported. In the first, complete mole with a co-existing live fetus was suspected on ultrasound examination at 16 weeks of gestation. A termination of pregnancy was performed due to early onset of severe preeclampsia and thyrotoxicosis. In the second case, the patient was admitted at 26 weeks of gestation due to preeclampsia. Genetic amniocentesis at 19 weeks of gestation revealed a normal 46 XX karyotype. Ultrasound examination at 21 weeks of gestation demonstrated two cystic lesions in the fetal liver, wide multicystic placenta and polyhydramnious. Following deteriorating severe preeclampsia, a live female infant (730 g) along with a huge placenta (1350 g) was delivered by a cesarean section. Unfortunately, the newborn died after 35 days. Pathological examination in both cases was consistent with a complete mole co-existing with a viable fetus. During a 1 year follow up period, there was no evidence of persistent or metastatic disease in both cases. Review of literature discussing the diagnostic tools, clinical features, management and outcome of pregnancies with complete mole with a co-existing live fetus is presented. [Copyright &y& Elsevier]

The article provides an analysis of preeclampsia, portliness, and perturbation of adipose tissue function. Topics include adipose tissue as a highly active endocrine organ, help in understanding of metabolic regulation of carbohydrates from discovery of adipokines, and challenge on prediction of preeclampsia and its pathophysiology.

Objective: The objective of the study was to determine whether eclampsia has a different circulating profile of angiogenic (placental growth factor [PlGF]) and antiangiogenic factors (soluble vascular endothelial growth factor receptor-1 [sVEGFR-1] and soluble endoglin [sEng]) from severe preeclampsia. Study Design: This cross-sectional study included pregnant women in the following groups: (1) normal pregnancy (n = 40); (2) severe preeclampsia (n = 40); and (3) eclampsia (n = 20). Maternal serum PlGF, sVEGFR-1, and sEng concentrations were determined using an enzyme-linked immunosorbent assay. Results: The study results included the following: (1) the median concentration of sVEGFR-1 and sEng was higher and of PlGF was lower in severe preeclampsia or eclampsia than in normal pregnancy (P < .001 for all); and (2) the median concentrations of these 3 analytes did not differ significantly between patients with severe preeclampsia and those with eclampsia. Conclusion: Eclampsia is associated with higher maternal circulating concentrations of sVEGFR-1 and sEng and lower concentrations of PlGF than normal pregnancy but with similar concentrations to severe preeclampsia. These findings suggest that eclampsia shares a common pathogenic pathway as severe preeclampsia. [ABSTRACT FROM AUTHOR]