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Abstract: Ischemic placental disease is a recently coined term that describes the vascular insufficiency now believed to be an important etiologic factor in preeclampsia, intrauterine fetal growth restriction, and placental abruption. Given the increased risk for poor maternal and fetal outcomes, early prediction and prevention of this disorder is of significant clinical interest for many. In this article, we review the second- and third-trimester serum and ultrasound markers predictive of ischemic placental disease. Limited first-trimester data is also presented. While current studies report a statistical association between marker levels and various adverse perinatal outcomes, the observed diagnostic accuracy is below the threshold required for clinical utility. An exception to this generalization is uterine artery Doppler for the prediction of early-onset preeclampsia. Metabolomics is a relatively new analytic platform that holds promise as a first-trimester marker for the prediction of both early- and late-onset preeclampsia. [Copyright &y& Elsevier]

Objective: The fetal inflammatory response syndrome (FIRS) is considered the fetal counterpart of the systemic inflammatory response syndrome (SIRS), which can be caused by infection and non-infection-related insults. Although the initial response is mediated by pro-inflammatory signals, the control of this response is achieved by anti-inflammatory mediators which are essential for the successful outcome of the affected individual. Interleukin (IL)-19 is capable of stimulating the production of IL-10, a major anti-inflammatory cytokine, and is a potent inducer of the T-helper 2 (Th2) response. The aim of this study was to determine if there is a change in umbilical cord plasma IL-19 and IL-10 concentrations in preterm neonates with and without acute funisitis, the histologic counterpart of FIRS. Methods: A case-control study was conducted including 80 preterm neonates born after spontaneous labor. Neonates were classified according to the presence ( n = 40) or absence of funisitis ( n = 40), which is the pathologic hallmark of FIRS. Neonates in each group were also matched for gestational age. Umbilical cord plasma IL-19 and IL-10 concentrations were determined by ELISA. Results: 1) The median umbilical cord plasma IL-19 concentration was 2.5-fold higher in neonates with funisitis than in those without funisitis (median 87 pg/mL; range 20.6-412.6 pg/mL vs. median 37 pg/mL; range 0-101.7 pg/mL; p < 0.001); 2) newborns with funisitis had a significantly higher median umbilical cord plasma IL-10 concentration than those without funisitis (median 4 pg/mL; range 0-33.5 pg/mL vs. median 2 pg/mL; range 0-13.8 pg/mL; p < 0.001); and 3) the results were similar when we included only patients with funisitis who met the definition of FIRS by umbilical cord plasma IL-6 concentrations ≥ 17.5 pg/mL ( p < 0.001). Conclusion: IL-19 and IL-10 are parts of the immunologic response of FIRS. A subset of fetuses with FIRS had high umbilical cord plasma IL-19 concentrations. In utero exposure to high systemic concentrations of IL-19 may reprogram the immune response. [ABSTRACT FROM AUTHOR]

Objective: To determine whether maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and -2 could identify patients at risk for developing preeclampsia (PE) requiring preterm delivery. Study design: Patients presenting with the diagnosis 'rule out PE' to the obstetrical triage area of our hospital at <37 weeks of gestation (n==87) were included in this study. Delivery outcomes were used to classify patients into four groups: I) patients without PE or those with gestational hypertension (GHTN) or chronic hypertension (CHTN) who subsequently developed PE at term ( n == 19); II): mild PE who delivered at term ( n == 15); III): mild disease (mild PE, GHTN, CHTN) who subsequently developed severe PE requiring preterm delivery ( n == 26); and IV): diagnosis of severe PE ( n == 27). Plasma concentrations of PlGF, sEng, sVEGFR-1 and -2 were determined at the time of presentation by ELISA. Reference ranges for analytes were constructed by quantile regression in our laboratory ( n == 180; 1046 samples). Comparisons among groups were performed using multiples of the median (MoM) and parametric statistics after log transformation. Receiver operating characteristic curves, logistic regression and survival analysis were employed for analysis. Results: The mean MoM plasma concentration of PlGF/sVEGFR-1, PlGF/sEng, PlGF, sVEGFR-1 and -2, and sEng in Group III was significantly different from Group II (all p < 0.05). A plasma concentration of PlGF/sVEGFR-1 ≤ 0.05 MoM or PlGF/sEng ≤0.07 MoM had the highest likelihood ratio of a positive test (8.3, 95% CI 2.8-25 and 8.6, 95% CI 2.9-25, respectively), while that of PlGF ≤0.396 MoM had the lowest likelihood ratio of a negative test (0.08, 95% CI 0.03-0.25). The association between low plasma concentrations of PlGF/sVEGFR-1 (≤0.05 MoM) as well as that of PlGF/sEng (≤0.07 MoM) and the development of severe PE remained significant after adjusting for gestational age at presentation, average systolic and diastolic blood pressure, and a history of chronic hypertension [adjusted odds ratio (OR) == 27 (95% CI 6.4-109) and adjusted OR 30 (95% CI 6.9-126), respectively]. Among patients who presented <34 weeks gestation ( n == 59), a plasma concentration of PlGF/sVEGFR-1 < 0.033 MoM identified patients who delivered within 2 weeks because of PE with a sensitivity of 93% (25/27) and a specificity of 78% (25/32). This cut-off was associated with a shorter interval-to-delivery due to PE [hazard ratio == 6 (95% CI 2.5-14.6)]. Conclusions: Plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in the obstetrical triage area. These observations support the value of these biomarkers in the clinical setting for the identification of the patient at risk for disease progression requiring preterm delivery. [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. Vaginal bleeding, placental abruption, and defective placentation are frequently observed in patients with preterm prelabor rupture of membranes (PROM). Recently, a role of vascular endothelial growth factor (VEGF) and its receptor, VEGF receptor (VEGFR)- 1 has been implicated in the mechanisms of membrane rupture. The purpose of this study was to determine whether the soluble form of VEGFR-1 and -2 concentrations in amniotic fluid (AF) change with preterm PROM, intra-amniotic infection/inflammation (IAI), or parturition. Study design. This cross-sectional study included 544 patients in the following groups: (1) midtrimester (MT) ( n = 48); (2) preterm labor (PTL) leading to term delivery ( n = 143); (3) PTL resulting in preterm delivery with ( n = 72) and without IAI ( n = 100); (4) preterm PROM with ( n = 46) and without IAI ( n = 42); (5) term in labor ( n = 48); and (6) term not in labor ( n = 45). The concentrations of sVEGFR-1 and sVEGFR-2 were determined by ELISA. Non-parametric statistics and logistic regression analysis were applied. Results. (1) Preterm PROM (with and without IAI) had a lower median AF concentration of sVEGFR-1 than patients with PTL who delivered at term ( p < 0.001 for each comparison); (2) A decrease in AFsVEGFR-1 concentrations per each quartile was associated with PROM after adjusting for confounders (OR 1.8; 95%CI 1.4–2.3); (3) IAI, regardless of the membrane status, was not associated with a change in the median AF concentrations of sVEGFR-1 and sVEGFR-2 ( p > 0.05 for each comparison); and (4) Spontaneous term and PTL did not change the median sVEGFR-1 and sVEGFR-2 concentrations ( p > 0.05 for each comparison). Conclusion. (1) This is the first evidence that preterm PROM is associated with a lower AF concentration of sVEGFR-1 than patients with PTL intact membranes. These findings cannot be attributed to gestational age, labor, or IAI; and (2) AF concentrations of sVEGFR-2 did not change with preterm PROM, IAI, or labor at term and preterm. [ABSTRACT FROM AUTHOR]

Management of pregnant patients with diabetes who have ischemic heart disease (IHD) remains a challenging clinical dilemma for obstetricians and maternal fetal specialist alike. The diagnosis of women with IHD is difficult, primarily because of a lack of awareness of the atypical characteristics at presentation by both patient and provider. Counseling of women regarding pregnancy when they are diabetic with IHD is best done before conception. Management by trimester should focus on careful monitoring of maternal cardiac status and stabilization of glycemic control without hypoglycemia. Delivery and postpartum care remain critical in the avoidance of complications and mortality., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: High mobility group box-1 (HMGB1) protein is an alarmin, a normal cell constituent, which is released into the extracellular environment upon cellular stress/damage and capable of activating inflammation and tissue repair. The receptor for advanced glycation end products (RAGE) can bind HMGB1. RAGE, in turn, can induce the production of pro-inflammatory cytokines; this may be modulated by the soluble truncated forms of RAGE, including soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE). The objectives of this study were to determine whether: 1) clinical chorioamnionitis at term is associated with changes in amniotic fluid concentrations of HMGB1, sRAGE and esRAGE; and 2) the amniotic fluid concentration of HMGB1 changes with labor or as a function of gestational age., Methods: Amniotic fluid samples were collected from the following groups: 1) mid-trimester (n = 45); 2) term with (n = 48) and without labor (n = 22) without intra-amniotic infection; and 3) term with clinical chorioamnionitis (n = 46). Amniotic fluid concentrations of HMGB1, sRAGE and esRAGE concentrations were determined by ELISA., Results: 1) the median amniotic fluid HMGB1 concentration was higher in patients at term with clinical chorioamnionitis than in those without this condition (clinical chorioamnionitis: median 3.8 ng/mL vs. term in labor: median 1.8 ng/mL, p = 0.007; and vs. term not in labor: median 1.1 ng/mL, p = 0.003); 2) in contrast, patients with clinical chorioamnionitis had a lower median sRAGE concentration than those without this condition (clinical chorioamnionitis: median 9.3 ng/mL vs. term in labor: median 18.6 ng/mL, p = 0.001; and vs. term not in labor median: 28.4 ng/mL, p < 0.001); 3) amniotic fluid concentrations of esRAGE did not significantly change in patients with clinical chorioamnionitis at term (clinical chorioamnionitis: median 5.4 ng/mL vs. term in labor: median 6.1 ng/mL, p = 0.9; and vs. term not in labor: median 9.5 ng/mL, p = 0.06); and 4) there was no significant difference in the median AF HMGB1 concentration between women at term in labor and those not in labor (p = 0.4) and between women in the mid-trimester and those at term not in labor (mid-trimester: median 1.5 ng/mL; p = 0.2)., Conclusion: An increase in the amniotic fluid HMGB1 concentration and a decrease in sRAGE were observed in clinical chorioamnionitis at term. This finding provides evidence that an alarmin, HMGB1, and one of its receptors, sRAGE, are engaged in the process of clinical chorioamnionitis at term. These changes are quite different from those observed in cases of intra-amniotic infection/inflammation in preterm gestations.

Objective: The fetal inflammatory response syndrome (FIRS) is associated with impending onset of preterm labor/delivery, microbial invasion of the amniotic cavity and increased perinatal morbidity. FIRS has been defined by an elevated fetal plasma interleukin (IL)-6, a cytokine with potent effects on the differentiation and proliferation of hematopoietic precursors. The objective of this study was to characterize the hematologic profile of fetuses with FIRS., Study Design: Fetal blood sampling was performed in patients with preterm prelabor rupture of membranes and preterm labor with intact membranes (n=152). A fetal plasma IL-6 concentration ≥ 11 pg/mL was used to define FIRS. Hemoglobin concentration, platelet count, total white blood cell (WBC) count, differential count, and nucleated red blood cell (NRBC) count were obtained. Since blood cell count varies with gestational age, the observed values were corrected for fetal age by calculating a ratio between the observed and expected mean value for gestational age., Results: 1) The prevalence of FIRS was 28.9% (44/152); 2) fetuses with FIRS had a higher median corrected WBC and corrected neutrophil count than those without FIRS (WBC: median 1.4, range 0.3-5.6, vs. median 1.1, range 0.4-2.9, P=0.001; neutrophils: median 3.6, range 0.1-57.5, vs. median 1.8, range 0.2-13.9, P<0.001); 3) neutrophilia (defined as a neutrophil count >95th centile of gestational age) was significantly more common in fetuses with FIRS than in those without FIRS (71%, 30/42, vs. 35%, 37/105; P<0.001); 4) more than two-thirds of fetuses with FIRS had neutrophilia, whereas neutropenia was present in only 4.8% (2/42); 5) FIRS was not associated with detectable changes in hemoglobin concentration, platelet, lymphocyte, monocyte, basophil or eosinophil counts; and 6) fetuses with FIRS had a median corrected NRBC count higher than those without FIRS. However, the difference did not reach statistical significance (NRBC median 0.07, range 0-1.3, vs. median 0.04, range 0-2.3, P=0.06)., Conclusion: The hematologic profile of the human fetus with FIRS is characterized by significant changes in the total WBC and neutrophil counts. The NRBC count in fetuses with FIRS tends to be higher than fetuses without FIRS.