| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
ORIGINAL RESEARCH |
From the Departments of Obstetrics and Gynecology and Medicine, University of Washington School of Medicine, Seattle, Washington; Department of Biostatistics, Columbia University, New York, New York; and Department of Biostatistics, Merck & Co., Inc., Rahway, New Jersey.
Address reprint requests to: Darcy B. Carr, MD, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Box 356460, Seattle, WA 98195-6460; E-mail: darcarr{at}u.washington.edu.
 |
ABSTRACT |
|---|
TOP
 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
METHODS: A controlled experimental study was performed for two groups: 1) women at risk for preeclampsia (high risk); and 2) women at low risk (controls). Tumor necrosis factor-
(TNF-), TNF- receptors 1 and 2, vascular cell adhesion molecule-1, cellular fibronectin, and cardiac output were measured at or before 24 weeks’ gestation and at 6–8 week intervals. High-risk subjects with cardiac output greater than 7.4 L/minute were treated with atenolol. Atenolol therapy was not randomized. Therefore, the longitudinal data were descriptive. Data were analyzed by the t test, Wilcoxon rank sum test, 
2 test, multivariable linear regression, and the standard two-stage test.
RESULTS: There were 46 high-risk subjects and 25 controls. Maternal age, gestational age, and parity did not differ between the groups. Cardiac output (P < .001) and vascular cell adhesion molecule-1 (P = .02) at baseline were significantly increased in the high-risk group. A total of 42 women in the high-risk group received atenolol for high cardiac output. There was a slower rise in TNF- receptor 1 in the treated group compared with the controls (P < .001).
CONCLUSION: Women with risk factors for preeclampsia had a hyperdynamic circulation and endothelial activation. Hemodynamically directed therapy in women at risk was associated with a slower rise in TNF- receptor 1 compared with low-risk women who were not treated, suggesting a relationship between hemodynamics and inflammatory activation.
Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality affecting 7–10% of pregnancies.1 Alterations in maternal hemodynamics,2,3 endothelial function,4–6 and the maternal inflammatory response7–9 occur early in the disease process. A hyperdynamic circulation characterized by high cardiac output is present in the pre-clinical phase of preeclampsia.2,3 Hemodynamically directed therapy is associated with a reduction in the rate of developing preeclampsia.10 Furthermore, elevated biochemical markers of endothelial4 and inflammatory activation7–9 have been demonstrated in the first and early second trimesters of women who later develop preeclampsia. These studies suggest that a hyperdynamic circulation, endothelial activation, and an excessive maternal inflammatory response have a role in the pathophysiology of preeclampsia.
We suspect that there is a relationship between a hyperdynamic circulation and the endothelial and inflammatory activation during pregnancy. To evaluate this relationship, we developed two hypotheses: 1) women who have clinical risk factors for preeclampsia will have a hyperdynamic circulation and elevated biochemical markers of endothelial and inflammatory activation; and 2) women with an abnormally elevated cardiac output who are treated with hemodynamically directed antihypertensive medication will have a change in these markers, suggesting a potential mechanism by which reducing cardiac output would decrease the risk of preeclampsia.
|
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
(TNF-), TNF- receptors 1 and 2, vascular cell adhesion molecule-1, and cellular fibronectin in two groups of women: 1) a group with clinical risk factors for preeclampsia (high-risk group); and 2) a group at low risk for preeclampsia (control group). Subjects in the high-risk group who had a second trimester cardiac output measurement greater than 7.4 L/minute underwent hemodynamically directed therapy with a ß-blocker (atenolol 50–100 mg daily). The cutoff for elevated cardiac output was determined from a prospective, longitudinal study that demonstrated an 18% risk of preeclampsia with cardiac output greater than 7.4 L/minute in the second trimester.2 The increased risk of preeclampsia based on this cutoff was confirmed in a double-blind, placebo-controlled study.10 The management of the high-risk subjects with elevated cardiac output was based on a double-blind, placebo-controlled study that revealed a reduction in the rate of preeclampsia in subjects treated with atenolol.10 These high-risk subjects who received atenolol therapy were considered the treatment group in the longitudinal analysis. No subjects in the control group received atenolol therapy. Because this was a nonrandomized study, the results from the longitudinal analysis of the two groups were descriptive and used to generate hypothesis regarding the role of abnormal hemodynamics and the alteration of endothelial and inflammatory activation. Investigational Review Board approval was obtained before recruiting subjects for enrollment. Women who received obstetric care at the University of Washington Maternal and Infant Care Clinic were invited to participate. Women were eligible for enrollment in the high-risk group if they had one or more of the following risk factors: prior pregnancy complicated by preeclampsia, obesity (weight greater than 84 kg or body mass index greater than 32 kg/m2), elevated second-trimester blood pressure (systolic blood pressure greater than or equal to 130 mmHg or diastolic blood pressure greater than or equal to 80 mmHg), and/or chronic hypertension. Women were eligible for enrollment in the control group if they had no medical complications and had a singleton gestation. Exclusion criteria for all subjects were antihypertensive therapy at the time of enrollment, immuno-suppression, autoimmune disease, clinical evidence of an infectious disease, multifetal gestation, and/or an anomalous fetus. Subjects were enrolled in the first or early second trimester (less than or equal to 24 weeks’ gestation) and were scheduled for study visits at approximately 6–8 week intervals (14–23, 24–29, 30–34, and greater than or equal to 35 weeks’ gestation).
Blood was drawn at each study interval for TNF-, TNF- receptors 1 and 2, vascular cell adhesion molecule-1, and cellular fibronectin. Chilled ethylenediamine tetraacetic acid tubes were used for collection of blood. The tubes were transported on ice and immediately centrifuged at 3200 x g for 6 minutes at 4C. The plasma was removed, aliquoted into cryotubes, and frozen at -70C within 30 minutes of collection. Assays for the biochemical markers were performed within 6 months of sample collection. Plasma levels of TNF- and TNF- receptors 1 and 2 were performed using an enzyme-linked immunosorbent assay technique as previously described.7 Interassay and intra-assay coefficients of variation for TNF- and TNF- receptors 1 and 2 were 3 10%. Assay sensitivities for TNF- and TNF- receptors 1 and 2 were 1 pg/mL, 2 pg/mL, and 8 pg/mL, respectively. Vascular cell adhesion molecule-1 measurements were performed with the enzyme-linked immunosorbent assay kit from R&D Systems (Minneapolis, MN). The interassay and intra-assay coefficients of variation for vascular cell adhesion molecule-1 were less than 10.3% and less than 6.0%, respectively. The sensitivity of this assay was less than 2 ng/mL. All samples, standards and controls, were run in duplicate. Cellular fibronectin was measured by radial immunodiffusion assay. The lower limit of detection for cellular fibronectin was 50 mg/L.
Blood pressure was measured using the Accutorr automated cuff (Datascope Corp., Paramus, NJ). Cardiac output was measured by Doppler technique using the UltraCOM Cardiac Output Monitor (Lawrence Medical, Redmond, WA) as previously described and validated against thermodilution technique in pregnant 11,12 and nonpregnant subjects.13–15 Total peripheral resistance = (80 x mean arterial pressure)/cardiac output.
Maternal age, parity, weight, gestational age, and mean arterial pressure were compared at enrollment. Continuous variables were analyzed by independent samples, two-tailed t test. Continuous variables that were not normally distributed were compared by the Wilcoxon rank sum test. Categorical variables were compared by 2 test or Fisher’s exact test.
To test our first hypothesis, multivariable linear regression was used to evaluate the association between group assignment (independent variable) and each hemodynamic measurement and each biochemical marker (dependent variables) at enrollment. Linear regression was also used to evaluate the association between hemodynamics measurements (independent variables) and biochemical markers (dependent variables). Logarithmic transformation of the dependent variables was performed to satisfy the necessary statistical assumptions of linear regression. Model building by the forward selection procedure was performed. Variables that were assessed for potential confounding were maternal age, gestational age, and primigravidity. Potential confounders were included if they changed the slope of the regression model by a minimum of 10%. Adjustment for confounders was performed in the final regression model.
To test the second hypothesis, the longitudinal data were evaluated by the standard two-stage method.16 A slope and intercept for each subject’s data were calculated by linear regression. The subjects’ slopes of cardiac output and each laboratory parameter were then compared between the treatment group and the control group by the two-tailed t test or Wilcoxon rank sum test. Because this controlled experimental study was not randomized, the treatment and control groups had different levels of risk for developing preeclampsia. To compare groups that were more similar for the risk of preeclampsia based on hemodynamic characteristics, a subanalysis was performed after dividing the control subjects into two groups based on cardiac output: a control group with cardiac output greater than 7.4 L/minute (high cardiac output control) and a control group with cardiac output less than or equal to 7.4 L/minute (normal cardiac output control). No subjects in the control groups received atenolol therapy.
A sample size estimate for detecting a difference of 90 pg/mL in TNF- receptor 1 between the groups at enrollment was performed based on published data by Williams et al, which demonstrated increasing odds ratios for developing preeclampsia as TNF- receptor 1 increased by increments of approximately 90 pg/mL.7 The standard deviations used in the sample size calculation for TNF- receptor 1 were 193.6 pg/mL for the high-risk group and 158.0 pg/mL for the control group.7 To detect a 90 pg/mL difference in enrollment TNF- receptor 1 levels, 45 women in the high-risk group and 23 women in the control group were needed for 80% power and a 5% significance level. We performed a sample size estimate for a 2:1 ratio of high-risk subjects to control subjects to ensure that we would enroll a sufficient number of high-risk subjects who would have elevated cardiac output and undergo hemodynamically directed therapy to evaluate the relationship between treatment and biochemical markers.
|
RESULTS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
). As expected, women in the high-risk group had increased mean arterial pressure and greater body weight than women in the control group (Table 1). Table 2 lists the means and standard deviations or the medians and ranges and the slopes for the baseline measurements as calculated by multivariable linear regression. Multivariable linear regression revealed a hyperdynamic circulation (elevated cardiac output and low total peripheral resistance) in the high-risk group as compared with the control group (Table 2). The variables included in the final model assessing the relationship between group and hemodynamics were maternal age, gestational age, and parity. The slope of -2.39 for cardiac output indicated that the control group had on average a cardiac output 2.39 L/minute less than the high-risk group (Table 2). Furthermore, vascular cell adhesion molecule-1 was increased in the high-risk group after adjusting for maternal age, gestational age, and parity in the final regression model (Table 2). Although the median values of TNF-, TNF- receptors 1 and 2, and cellular fibronectin appeared greater in the high-risk group, the differences were not statistically significant (Table 2). The variables in the final regression models for TNF- and TNF- receptor 2 included maternal age, gestational age, and parity. The final model for TNF- receptor 1 included gestational age and parity. The final model for cellular fibronectin included gestational age. No significant linear relationships between enrollment hemodynamics and biochemical markers were demonstrated by multivariable linear regression.
|
|
and TNF- receptor 2 were not performed because many subjects had undetectable levels. In the high-risk group, 42 of 46 subjects met criteria for hemodynamically directed antihypertensive therapy and were included in the longitudinal analyses as the treatment group. Four high-risk subjects were not eligible for treatment for the following reasons: one subject moved to another state and was not able to continue participating in the study, two had normal hemodynamic measurements, and one refused therapy. One control subject had a spontaneous abortion after the baseline evaluation. Therefore, 24 of the 25 control subjects had data available for the longitudinal analysis. A total of 44% of subjects had four or more study visits, and 45% had three measurement points, which were at the following intervals: first- to early second-trimester gestational age, 24–29 weeks’ gestation, and greater than or equal to 35 weeks’ gestation. Only seven subjects (approximately 11%) had two study visits because of either early delivery or missed appointments.
Descriptive results for the longitudinal analyses are presented in Figures 1–4. The change in cardiac output over pregnancy was significantly different between the groups (P < .001, Figure 1). Women in the treatment group who received hemodynamically directed therapy had a decrease in cardiac output compared with women in the control group (Figure 1). The rise in TNF- receptor 1 was significantly slower in the treatment group compared with the controls (P < .001, Figure 2). The vascular cell adhesion molecule-1 slopes for the treatment group compared with the control group were not statistically different (P = .8, Figure 3). Similarly, the slopes of cellular fibronectin for the treatment group compared with the control group were not statistically different (P = .02, Figure 4).
|
|
|
|
receptor 1 during pregnancy as compared with the high cardiac output controls (P = .001) and normal cardiac output controls (P = .02, Figure 2
). The slopes for vascular cell adhesion molecule-1 and cellular fibronectin were not significantly different between the treatment and control groups (Figures 3 and 4).
Pregnancy outcomes between the high-risk and control groups are listed in Table 3. There was no significant difference between gestational age at delivery (P = .06). Although the average birth weight (P < .001) and birth weight percentile (P < .001) were less in the high-risk group, the rate of growth restriction (birth weight less than 10th percentile) was not significantly different between the groups (P = .2). Preeclampsia was diagnosed in 4.4% of the subjects in the high-risk group and 4.3% of the controls. All subjects who developed preeclampsia had baseline cardiac output measurements greater than or equal to 8.3 L/minute.
|
|
DISCUSSION |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
This current study described the relationship between hemodynamics and plasma markers of endothelial and inflammatory activation during pregnancy. Women with clinical risk factors for preeclampsia had a hyperdynamic circulation in the first or early second trimester compared with women at low risk for preeclampsia. These women had evidence of increased endothelial activation as assessed by measuring plasma vascular cell adhesion molecule-1. The relationship between the hyperdynamic circulation and endothelial activation was described longitudinally by using atenolol as an interventional tool to normalize the high cardiac output and examine the pattern of these biochemical markers during pregnancy. The rationale for using atenolol was based on the previous intervention study by Easterling et al.10 Furthermore, atenolol would serve as an appropriate interventional tool for evaluating the relationship between hemodynamics and biochemical markers because it is a selective antagonist to the ß1-adrenergic receptor and does not directly regulate cytokine production.17–19 Women with risk factors for preeclampsia who received atenolol therapy for high cardiac output demonstrated a slower rise in TNF- receptor 1 during pregnancy compared with controls. Because this was not a randomized study, the treatment and control groups differed in their risk factors for preeclampsia. To create groups that were similar for the hemodynamic abnormality, a subgroup analysis was performed using controls that had high cardiac output. This analysis also confirmed the finding of a slower rise in TNF- receptor 1 in women treated with atenolol. Although the subgroup analysis formed more comparable groups, the study was not designed to test the efficacy of atenolol in altering biochemical markers of inflammatory and endothelial activation.
Despite these study design limitations, the results can be used to generate the hypothesis that the hemodynamic status in pregnancy is associated with the degree of inflammatory activation as assessed by TNF- receptor 1. Tumor necrosis factor- activates the endothelium primarily through TNF- receptor 1.20 Therefore, this slower rise in TNF- receptor 1 may reflect an improvement in the inflammatory status of the endothelium as women with a hyperdynamic circulation are treated with atenolol, suggesting a possible mechanism by which hemodynamically directed therapy may reduce the risk of preeclampsia. A randomized study of hemodynamically directed therapy on biochemical markers during pregnancy would further explore this mechanism.
Plasma levels of biochemical markers may not accurately reflect the functional state of these substances because they may primarily act in an autocrine or paracrine manner and have brief half-lives. However, an advantage of plasma measurements is that they allow the investigation of the relationship between hemodynamics and endothelial and inflammatory activation during pregnancy using minimally invasive procedures. Tumor necrosis factor- was measured because it is a first-order proinflammatory cytokine, which is elevated early during pregnancy in women who develop preeclampsia.7,9 Because TNF- has a very short half-life, TNF- receptors 1 and 2 were measured as biological markers of TNF- release. Plasma levels of vascular cell adhesion molecule-1 and cellular fibronectin were measured to assess endothelial activation and injury. These markers are also elevated early in pregnancy in women who develop preeclampsia.4–6 Despite the potential limitations and difficulty in detecting these substances, investigators have successfully measured plasma levels of these markers using the techniques described in this study and have found differences between women who develop preeclampsia and women who remain normotensive during pregnancy.4,6,7,9
Plasma levels of TNF- receptor 1 and cellular fibronectin were not different between women with risk factors and the controls at the time of enrollment. There were more primigravid women in the control group. Because primigravidity could affect the markers of inflammatory activation, it was included in the multivariate linear regression analyses as a potential confounder. However, adjusting for parity did not demonstrate a significant difference in inflammatory markers between the groups. It is possible that the study lacked the power to detect significant differences in TNF- receptor 1 and cellular fibronectin between the groups. Even though a sample size calculation was performed, the estimate was based on a study that evaluated the second-trimester levels of TNF- receptor 1 in women who later developed preeclampsia to determine if it was a predictor of preeclampsia.7 The specific aims of the present study were not to determine TNF- receptor 1 levels in women who later developed preeclampsia, but rather to compare levels between women with risk factors and women at low risk for preeclampsia. Therefore, the differences in TNF- receptor 1 reported in the study by Williams et al were likely greater than what would be expected in this present study.7 Choosing to detect a smaller difference in TNF- receptor 1 or using 90% power in the sample size calculation would have required a larger sample size and may have led to a statistically significant finding.
The pregnancy outcomes between the groups were not significantly different except for birth weight and birth weight percentile. Women in the high-risk group had a lower median birth rate percentile (27.4%). Most of these women (91.3%) received treatment for a hyper-dynamic circulation and experienced a reduction in cardiac output. The reduction in cardiac output in this group may explain some of the decrease in birth weight percentile. There are other variables present in the high-risk group that may contribute to the decreased birth weight percentile, such as a prior history of fetal growth restriction, prior severe preeclampsia, and chronic hypertension. However, this study was not designed to evaluate the relationships between birth weight percentile and risk factors for a reduction in weight. The presence of these potential confounders, which were not evaluated in this study, makes it difficult to develop inferences regarding the birth weight percentile data. Of clinical importance, there was not an increased rate of fetal growth restriction (birth weight less than 10th percentile) in the high-risk group compared with the control group. Furthermore, despite risk factors for preeclampsia and treatment with atenolol, the rate of fetal growth restriction in the high-risk group (11.1%) is consistent with what would be expected in a normal population.
Although the predicted risk for preeclampsia in the high-risk group was 18%,2,10 the rate of preeclampsia was no different than that in the control group. The low rate of preeclampsia in the treatment group may reflect the use of atenolol for the prevention of preeclampsia in women who have risk factors and a hyperdynamic circulation. A similar reduction in the rate of preeclampsia with atenolol therapy was demonstrated in a double-blind, placebo-controlled study.10 Because this present study was not designed to evaluate the prevention of preeclampsia with atenolol therapy, conclusions regarding its efficacy would not be appropriate from the data.
This study investigated the relationship between maternal hemodynamics and biochemical markers of endothelial and inflammatory activation in women with risk factors and in women at low risk for preeclampsia. Women with clinical risk factors for preeclampsia had a hyperdynamic circulation and elevated levels of vascular cell adhesion molecule-1 compared with women at low risk for preeclampsia. To further describe the relationship between hemodynamics and these markers, atenolol was used as an interventional tool. Women who received atenolol demonstrated a decrease in cardiac output during pregnancy and a slower rise in TNF- receptor 1 compared with women who were not treated. These longitudinal data suggest a relationship between hemodynamic status and markers of endothelial and inflammatory activation during pregnancy.
|
Footnotes |
|---|
Received February 27, 2001. Received in revised form June 7, 2001. Accepted July 26, 2001.
|
REFERENCES |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
2. Easterling T, Benedetti T, Schmucker B, Millard S. Maternal hemodynamics in normal and preeclamptic pregnancies: A longitudinal study. Obstet Gynecol 1990;76: 1061–9.
3. Bosio PM, McKenna PJ, Conroy P, O’Herlihy R. Maternal central hemodynamics in hypertensive disorders of pregnancy: A longitudinal study. Obstet Gynecol 1999;94: 978–84.
4. Krauss T, Kuhn W, Lakoma C, Augustin H. Circulating endothelial cell adhesion molecules as diagnostic markers for the early identification of pregnant women at risk for development of preeclampsia. Am J Obstet Gyecol 1997; 177:443–9.
5. Lockwood C, Peters J. Increased plasma levels of ED1+ cellular fibronectin precede the clinical signs of preeclampsia. Am J Obstet Gynecol 1990;162:358–62.[Medline]
6. Paarlberg K, de Jong C, van Geijn H, van Kamp G, Heinen A, Dekker G. Total plasma fibronectin as a marker of pregnancy-induced hypertensive disorders: A longitudinal study. Obstet Gynecol 1998;91:383–8.[Abstract]
7. Williams MA, Farrand A, Mittendorf R, Sorensen TK, Zingheim RW, O’Reilly GC, et al. Maternal second trimester serum tumor necrosis factor-alpha-soluble receptor p55 (sTNFp55) and subsequent risk of preeclampsia. Am J Epidemiol 1999;149:323–9.
8. Eneroth E, Remberger M, Vahlne A, Ringden O. Increased serum concentrations of interleukin-2 receptor in the first trimester in women who later developed severe preeclampsia. Acta Obstet Gynecol Scand 1998;77:591–3.[Medline]
9. Hamai Y, Fujii T, Yamashita T, Nishina H, Kazuma S, Mikami Y, et al. Evidence for an elevation in serum interleukin-2 and tumor necrosis factor-alpha levels before the clinical manifestations of preeclampsia. Am J Reprod Immunol 1997;38:89–93.
10. Easterling T, Brateng D, Schmucker B, Brown Z, Millard S. Prevention of preeclampsia: A randomized trial of atenolol in hyperdynamic patients before onset of hypertension. Obstet Gynecol 1999;93:725–33.
11. Easterling T, Watts D, Schmucker B, Benedetti T. Measurement of cardiac output during pregnancy: Validation of Doppler technique and clinical observations in pre-eclampsia. Obstet Gynecol 1987;69:845–50.[Medline]
12. Easterling T, Carlson K, Schmucker B, Brateng D, Benedetti T. Measurement of cardiac output in pregnancy by Doppler technique. Am J Perinatol 1990;7:220–2.[Medline]
13. Chandraratna P, Nanna M, McKay C, Nimalasuriya A, Swinney R, Elkayam U, et al. Determination of cardiac output by transcutaneous continuous-wave ultrasound Doppler computer. Am J Cardiol 1984;53:234–7.[Medline]
14. Huntsman L, Stewart D, Barnes S, Franklin S, Colocousis J, Hessel E. Noninvasive Doppler determination of cardiac output in man: Clinical validation. Circulation 1983;67: 593–602.
15. Nishmura R, Callaham M, Schaff H, Ilstrung D, Miller F, Tajik A. Noninvasive measurement of cardiac output by continuous-wave Doppler echocardiography: Initial experience and review of the literature. Mayo Clin Proc 1984; 509:484–9.
16. Feldman H. Families of lines: Random effects in linear regression analysis. J Appl Physiol 1988;64:1721–31.
17. Nakamura A, Johns E, Imaizumi A, Abe T, Kahsaka T. Regulation of tumor necrosis factor and interleukin-6 gene transcription by beta2-adrenoceptor in the rat astrocytes. J Neuroimmunol 1998;88:144–53.[Medline]
18. Nakamura A, Johns E, Imaizumi A, Yanagawa Y, Kohsaka T. Effect of beta(2)-adrenoceptor activation and angiotensin II on tumor necrosis factor and interleukin 6 gene transcription in the rat renal resident macrophage cells. Cytokine 1999;11:759–65.[Medline]
19. Izeboud C, Mocking J, Monshouwer M, van Miert A, Witkamp R. Participation of beta-adrenergic receptors on macrophages in modulation of LPS-induced cytokine release. J Recept Signal Transduct Res 1999;19:191–202.[Medline]
20. Paleolog E, Dekasalle S, Buurman W, Feldmann M. Functional activities of receptors for tumor necrosis factor-alpha on human vascular endothelial cells. Blood 1994;84: 2578–90.
This article has been cited by other articles:
|
|
 |
|
  M. Hladunewich, S. A. Karumanchi, and R. Lafayette Pathophysiology of the Clinical Manifestations of Preeclampsia Clin. J. Am. Soc. Nephrol., May 1, 2007; 2(3): 543 - 549. [Full Text] [PDF]
|
|
|
|
 |
|
 I. Alacacioglu, M. A. Ozcan, O. Piskin, F. Yuksel, A. Alacacioglu, F. Demirkan, H. G. Ozsan, M. Polat, Y. Ozgenc, and B. Undar Increased Concentration of Soluble CD40 Ligand in Preeclampsia Clinical and Applied Thrombosis/Hemostasis, April 1, 2007; 13(2): 201 - 205. [Abstract] [PDF]
|
|
|
|
 |
|
 G. Mello, E. Parretti, C. Fatini, C. Riviello, F. Gensini, M. Marchionni, G. F. Scarselli, G. F. Gensini, and R. Abbate Low-Molecular-Weight Heparin Lowers the Recurrence Rate of Preeclampsia and Restores the Physiological Vascular Changes in Angiotensin-Converting Enzyme DD Women Hypertension, January 1, 2005; 45(1): 86 - 91. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
