Beth L. Pineles

First-trimester maternal serum PP13 in the risk assessment for preeclampsia

OBJECTIVE The objective of the study was to determine whether first-trimester maternal serum placental protein 13 (PP13) concentrations can be used in the risk assessment for preeclampsia. STUDY DESIGN This case-control study included 50 patients with preeclampsia and 250 patients with normal pregnancies. Samples were collected between 8 and 13 weeks of gestation. Serum PP13 concentrations were measured by immunoassay and expressed as medians and multiples of the median (MoM) for gestational age. Sensitivity and specificity were derived from receiver-operating characteristic curve analysis. RESULTS (1) Serum PP13 concentration in the first trimester was significantly lower in patients who developed preterm and early-onset preeclampsia than in those with normal pregnancies; and (2) at 80% specificity, a cutoff of 0.39 MoM had a sensitivity of 100% for early-onset preeclampsia and 85% for preterm preeclampsia. CONCLUSION Maternal serum first-trimester PP13 appears to be a reasonable marker for risk assessment for preterm preeclampsia but a weak marker for severe preeclampsia at term, and ineffective for identifying mild preeclampsia at term.

Plasma adiponectin concentrations in non-pregnant, normal and overweight pregnant women.

Abstract Aims: Adiponectin is an adipokine that has anti-diabetic, anti-atherogenic, anti-inflammatory and angiogenic properties. This hormone has been implicated in both the physiological adaptation to normal pregnancy and in obstetrical complications. The aims of this study were to determine normal maternal plasma concentrations of adiponectin throughout gestation and to explore the relationships between plasma adiponectin concentration, pregnancy, and maternal overweight. Methods: A cross-sectional study was designed to include normal pregnant (normal weight and overweight; 11–42 weeks of gestation), and non-pregnant women. Plasma adiponectin concentration was determined by immunoassay. Non-parametric statistics were used for analysis. Results: (1) Adiponectin was detectable in the plasma of all patients; (2) there was no significant differences in the median adiponectin concentration between pregnant and non-pregnant women; (3) plasma adiponectin concentrations were negatively correlated with gestational age only among normal weight pregnant women; and (4) overweight patients had significantly lower plasma adiponectin concentrations than normal weight women. Conclusions: Consistent with the increased insulin resistance and weight gain that occur in pregnancy, adiponectin concentrations were negatively correlated with gestational age. The results of this study and the nomogram herein presented, can serve as the basis to explore the relationship between adiponectin and pregnancy complications and facilitate the clinical use of this important adipokine.

Low maternal concentrations of soluble vascular endothelial growth factor receptor-2 in preeclampsia and small for gestational age

Objectives. Preeclampsia is considered an anti-angiogenic state. A role for the anti-angiogenic factors soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and soluble endoglin in preeclampsia has been proposed. Soluble vascular endothelial growth factor receptor-2 (sVEGFR-2) has been detected in human plasma, and the recombinant form of this protein has anti-angiogenic activity. There is a paucity of information about maternal plasma sVEGFR-2 concentrations in patients with preeclampsia and those without preeclampsia with small for gestational age (SGA) fetuses. This study was conducted to determine whether: (1) plasma sVEGFR-2 concentration changes throughout pregnancy; and (2) preeclampsia and SGA are associated with abnormalities in the maternal plasma concentration of sVEGFR-2. Study design. This cross-sectional study included non-pregnant women (n = 40), women with normal pregnancies (n = 135), women with an SGA fetus (n = 53), and women with preeclampsia (n = 112). SGA was defined as an ultrasound-estimated fetal weight below the 10th percentile for gestational age that was confirmed by neonatal birth weight. Plasma concentrations of sVEGFR-2 were determined by ELISA. Results. (1) There was no significant difference in the mean plasma concentration of sVEGFR-2 between non-pregnant women and those with normal pregnancies (p = 0.8); (2) patients with preeclampsia and those without preeclampsia with SGA fetuses had a lower mean plasma concentration of sVEGFR-2 than that of women with normal pregnancies (p < 0.001 for both); and (3) there was no significant difference in the mean plasma concentration of sVEGFR-2 between patients with preeclampsia and those without preeclampsia with SGA (p = 0.9). Conclusions. Preeclampsia and SGA are associated with low plasma concentrations of sVEGFR-2. One interpretation of the findings is that plasma sVEGFR-2 concentration could reflect endothelial cell function.

Adiponectin in severe preeclampsia.

Abstract Aims: Adiponectin is an adipokine with insulin-sensitizing, anti-atherogenic, anti-inflammatory and angiogenic properties. The aims of this study were to determine whether maternal plasma adiponectin concentrations differ between patients with severe preeclampsia and those with normal pregnancies, and to explore the relationship between plasma adiponectin and the results of Doppler velocimetry of the uterine arteries. Methods: This case-control study included two groups: (1) patients with severe preeclampsia (n=50) and (2) patients with normal pregnancies (n=150). Pulsed-wave and color Doppler ultrasound examination of the uterine arteries were performed. Plasma adiponectin concentrations were determined by ELISA. Non-parametric statistics were used for analysis. Results: (1) Patients with severe preeclampsia had a higher median plasma concentration of adiponectin than that of normal pregnant women. (2) The median plasma adiponectin concentration did not differ between women with severe preeclampsia who had a high impedance to blood flow in the uterine arteries and those with normal impedance to blood flow. (3) Among patients with normal pregnancies, plasma adiponectin concentrations were negatively correlated with BMI in the first trimester and at sampling. Conclusions: Women with severe preeclampsia have a higher median plasma concentration of adiponectin than that of normal pregnant women. This may reflect a compensatory feedback mechanism to the metabolically-altered, anti-angiogenic and pro-atherogenic state of severe preeclampsia.

Resistin: a hormone which induces insulin resistance is increased in normal pregnancy.

Abstract Aims: Resistin, a newly discovered adipokine, is thought to play a key role in the regulation of insulin resistance. The objectives of this study were to develop a nomogram of maternal plasma concentrations of resistin from 11 weeks of gestation to term and to determine whether resistin concentrations differ between normal and overweight pregnant women. Methods: In this cross-sectional study, plasma concentrations of resistin were determined in normal pregnant women of normal body mass index (BMI 18.5–24.9; n=261), overweight pregnant women (BMI ≥25; n=140), and non-pregnant women of normal BMI (n=40). Blood samples were collected once from each woman between the first trimester and term. Percentiles for resistin concentration were determined for five pre-specified windows of gestational age. Plasma resistin concentration was determined by immunoassay. Non-parametric statistics were used for analysis. Results: The median maternal plasma concentration of resistin between 11 to 14 weeks of gestation in women of normal weight was significantly higher than non-pregnant women; the plasma concentration of resistin increased with gestational age. Conclusions: Normal pregnant women have a higher median plasma concentration of resistin than non-pregnant women and the concentration of this adipokine increases with advancing gestation. Alterations in the maternal plasma concentration of resistin during pregnancy could contribute to metabolic changes of pregnancy.

Over-expression of the thrombin receptor (PAR-1) in the placenta in preeclampsia: A mechanism for the intersection of coagulation and inflammation

Objective. Preeclampsia (PE) is characterized by excessive thrombin generation, which has been implicated in the multiple organ damage associated with the disease. The biological effects of thrombin on coagulation and inflammation are mediated by protease-activated receptor-1 (PAR-1), a G protein-coupled receptor. The aim of this study was to determine whether preterm PE is associated with changes in placental expression of PAR-1. Study design. This cross-sectional study included two groups matched for gestational age at delivery: (1) patients with preterm PE (<37 weeks of gestation; n = 26) and (2) a control group of patients with preterm labor without intra-amniotic infection (n = 26). Placental tissue microarrays were immunostained for PAR-1. Immunoreactivity of PAR-1 in the villous trophoblasts was graded as negative, weak-positive, or strong-positive. Results. (1) The proportion of cases with strong PAR-1 immunoreactivity was significantly higher in placentas of patients with PE than in placentas from the control group (37.5% (9/24) vs. 8.7% (2/23); p = 0.036, respectively). (2) PAR-1 immunoreactivity was found in the cellular compartments of the placental villous tree, mainly in villous trophoblasts and stromal endothelial cells. (3) PAR-1 was detected in 92.3% (24/26) of the placentas of women with PE and in 88.5% (23/26) of the placentas from the control group. Conclusion. Placentas from pregnancies complicated by preterm PE had a significantly higher frequency of strong PAR-1 expression than placentas from women with spontaneous preterm labor. This observation is consistent with a role for PAR-1 as a mediator of the effect of thrombin on coagulation and inflammation in PE. We propose that the effects of thrombin in PE are due to increased thrombin generation and higher expression of PAR-1, the major receptor for this enzyme.

Preeclampsia is associated with low concentrations of protein Z.

Objective. Protein Z, a vitamin K-dependent plasma protein, has an important role in the regulation of the coagulation cascade. Protein Z deficiency has been associated with unexplained pregnancy loss and adverse pregnancy outcome in patients with thrombophilia. This study was conducted to determine if preeclampsia (PE), small for gestational age (SGA), and fetal demise are associated with changes in maternal plasma concentrations of protein Z. Study design. This cross-sectional study included normal pregnant women (N = 71), patients with PE (N = 130), patients who delivered an SGA neonate (N = 58), and patients with fetal demise (N = 58). Maternal plasma protein Z concentrations were measured by a sensitive and specific immunoassay. Protein Z deficiency was defined as maternal plasma concentrations ≤5th percentile of the normal pregnancy group (≤1.59 µg/mL). Non-parametric statistics were used for analysis. Results. (1) Patients with PE had a lower median plasma concentration of protein Z than normal pregnant women (PE: median 1.6 µg/mL, range 0.2–3.3 µg/mL vs. normal pregnancy: median 2.4 µg/mL, range 1.1–3.4 µg/mL; p < 0.0001); (2) patients with an SGA neonate (median 2.3 µg/mL, range 0.2–3.8 µg/mL) and fetal demise (median 2.6 µg/mL, range 0.2–4.3 g/mL) did not have significantly different median protein Z concentrations from normal pregnant women (p > 0.05); and (3) women in the PE and fetal demise groups had significantly higher rates of protein Z deficiency than those with normal pregnancy outcome. Conclusions. (1) PE, but not SGA or fetal demise, is associated with a significantly lower maternal median plasma concentration of protein Z than normal pregnancy, and (2) a high rate of protein Z deficiency is observed in patients with PE and fetal demise.

Chorioamnionitis and increased galectin-1 expression in PPROM - An anti-inflammatory response in the fetal membranes?

Problem Galectin‐1 can regulate immune responses upon infection and inflammation. We determined galectin‐1 expression in the chorioamniotic membranes and its changes during histological chorioamnionitis.

Pyelonephritis during pregnancy: A cause for an acquired deficiency of protein Z

Objective. Pyelonephritis has a more severe course during pregnancy than in the non-pregnant state. This has been attributed to the increased susceptibility of pregnant women to microbial products. An acquired protein Z deficiency has been reported when there is excessive thrombin activity. The aim of this study was to determine whether pyelonephritis during pregnancy is associated with changes in maternal plasma protein Z concentrations. Study design. A cross-sectional study was conducted to compare plasma protein Z concentrations between normal pregnant women (N = 71) and pregnant women with pyelonephritis (N = 42). Protein Z concentrations were measured by enzyme-linked immunosorbent assay. Parametric and non-parametric statistics were used for analysis. Results. Patients with pyelonephritis had a significantly lower median plasma concentration of protein Z than did patients with normal pregnancies (median 2.14 μg/mL (0.4–3.4) vs. median 2.36 μg/mL (1.09–3.36); p = 0.03). There was no difference in the median plasma concentration of anti-protein Z antibodies between patients with pyelonephritis and those with normal pregnancies. Conclusion. The median maternal plasma protein Z concentration was significantly lower in patients with pyelonephritis during pregnancy than in patients with normal pregnancies.

The timed-pregnant baboon animal model can be used for determining the role of soluble vascular endothelial growth factor receptors 1 and 2 during development

Background  During pregnancy, mechanisms that allow for regulation of continuous fetal and placental vasculogenesis with prevention of maternal neo‐vascularization remain elusive. The vascular endothelial growth factor (VEGF) biological system has a key role during vasculogenesis. The aims of this study were to validate a bioassay for soluble vascular endothelial growth factor receptors 1 and 2 (sVEGFR‐1 and sVEGFR‐2) in baboon plasma and to determine the maternal and fetal plasma concentration of these receptors at the end of the baboon pregnancy.