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Obstetrics & Gynecology:
Original Research

Increased Endothelial Monocyte Chemoattractant Protein‐1 and Interleukin‐8 in Preeclampsia

Kauma, Scott MD; Takacs, Peter MD; Scordalakes, Constantine MD; Walsh, Scott PhD; Green, Kermic; Peng, Thomas MD

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Author Information

Department of Obstetrics and Gynecology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia.

Address reprint requests to: Scott Kauma, MD, Virginia Commonwealth University, Medical College of Virginia, Department of Obstetrics and Gynecology, 1101 East Marshall Street, Sanger Hall, Room 11–029, Box 980034, Richmond, VA 23298; E‐mail: skauma@hsc.vcu.edu.

This work was supported in part by a Clinical Research Center Grant (MO1‐RR00065, National Center for Research Resources, National Institutes of Health) and by grants from the National Institute of Child Health and Human Development to SK (R01 HD35640, K24 HD40252).

Received December 7, 2001. Received in revised form April 5, 2002. Accepted April 25, 2002.

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Abstract

OBJECTIVE: To test the hypothesis that preeclampsia is associated with increased endothelial cell chemokine production of monocyte chemoattractant protein‐1 and interleukin‐8 necessary for monocyte recruitment to the vascular endothelium.

METHODS: Plasma was collected from women with severe preeclampsia and normal pregnant women at term and measured for monocyte chemoattractant protein‐1, interleukin‐8, and lipid peroxide levels by enzyme‐linked immunosorbent assays and malondialdehyde assays. Human umbilical vein endothelial cells were cultured with 5% plasma from normal or preeclamptic patients and the media assayed for monocyte chemoattractant protein‐1 and interleukin‐8 production.

RESULTS: In women with severe preeclampsia, plasma levels of monocyte chemoattractant protein‐1, interleukin‐8, and lipid peroxides were elevated (1.5‐fold, 2.5‐fold, and 4.5‐fold higher, respectively) compared with normal pregnant women. Human umbilical vein endothelial cells cultured with plasma from preeclamptic women significantly increased the production of both monocyte chemoattractant protein‐1 (2.3‐fold) and interleukin‐8 (1.5‐fold) compared with plasma from normal pregnant women. Monocyte chemoattractant protein‐1 and interleukin‐8 production was decreased by the antioxidant vitamin E in human umbilical vein endothelial cells treated with preeclamptic plasma, suggesting that the production of these cytokines may be regulated by signaling mechanisms sensitive to oxidative stress.

CONCLUSION: These findings support the hypothesis that circulating factors in the plasma of women with preeclampsia activate endothelial cell monocyte chemoattractant protein‐1 and interleukin‐8 production, and although not directly examined in this study, may increase monocyte adherence to the vascular endothelium.

Preeclampsia is a pregnancy‐specific disorder with an incidence of 6–8% in the United States and is an important cause of maternal and fetal morbidity and mortality.1 Maternal risk factors for the development of preeclampsia are obesity, hypertension, insulin resistance, and hyperlipidemia.2,3 Preeclampsia is a systemic disease characterized by maternal hypertension, proteinuria, edema, and in some women, activation of the coagulation system. Most of these clinical pathologic findings in preeclampsia can be attributed to abnormalities in vascular endothelial activation or dysfunction.4,5 Consequently, the pathogenic mechanisms of preeclampsia converge on the vascular endothelium.

A potential factor leading to endothelial cell dysfunction in preeclampsia is increased oxidative stress. Evidence has accumulated that women with preeclampsia have increased circulating levels of oxygen‐free radicals and lipid peroxides.6,7 Conversely, there are decreased levels of circulating antioxidants such as vitamin E.8 Numerous studies point to lipid peroxides, oxidized lipids, and oxidative stress as important mediators of endothelial cell dysfunction not only in preeclampsia, but also in atherosclerotic cardiovascular disease.9 Some women with preeclampsia share many of the same risk factors associated with atherosclerotic heart disease including hyperlipidemia, hypertension, and obesity, all conditions associated with increased lipid peroxides and oxidative stress.2 The presence of “acute atherosis” in the spiral arteries of some women with preeclampsia further supports the commonality between endothelial dysfunction in preeclampsia and atherosclerosis.10,11 These findings suggest that models of lipid peroxide‐induced endothelial dysfunction in atherosclerosis may be useful in the study of endothelial dysfunction in preeclampsia.

A potential mechanism for vascular endothelial activation in preeclampsia is through nuclear transcription factor‐κB, which can be activated by lipid peroxides, oxidative stress, and proinflammatory cytokines.12,13 A recent study in our laboratory demonstrated that increased circulating lipid peroxides in women with preeclampsia induce endothelial intracellular adhesion molecule‐1 expression through a nuclear transcription factor‐κB‐mediated mechanism.14 Endothelial nuclear transcription factor‐κB activation by oxidative stress also induces the expression of several chemokines such as monocyte chemoattractant protein‐1 and interleukin‐8 in in vitro models of atherosclerosis.15 Activation of circulating monocytes by endothelial chemokines along with increased endothelial intracellular adhesion molecule‐1 expression is thought to result in increased adherence of monocytes to vascular endothelial cells and the presence of numerous macrophages in atherosclerotic lesions.16,17 A similar process could account for the presence of “acute atherosis” seen in preeclampsia.10,11

The purpose of this study was to determine if circulating levels of monocyte chemoattractant protein‐1 and interleukin‐8 were elevated in women with severe preeclampsia and if factors in the plasma from severe preeclamptic women activate vascular endothelial cell production of these chemokines. Furthermore, because a recent clinical study suggests that antioxidant therapy decreases the incidence of preeclampsia in women at high risk, we also determined if vitamin E could effectively inhibit monocyte chemoattractant protein‐1 and interleukin‐8 production in vascular endothelial cells.

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MATERIALS AND METHODS

Patients for this study were recruited at the time of admission to labor and delivery over an 8‐month period. All patients admitted to our labor and delivery suite with a diagnosis of severe preeclampsia were asked to participate in this study, and approximately 70% agreed to participate. Normal pregnant women were recruited on an intermittent basis during this same time, and approximately 20% of normal patients agreed to participate in this study. Blood samples were collected into standard sodium heparin‐coated tubes from women with normal term pregnancies (n = 12) and from women with severe preeclampsia (n = 12) upon admission to labor and delivery. Informed consent was obtained from each patient, and the protocol was approved by the Institutional Internal Review Board of Virginia Commonwealth University and Western Institutional Review Board. The procedures followed were in accordance with the ethical standards for human experimentation established by the Declaration of Helsinki of 1975, revised in 1983. Normal pregnant women were recruited who had no chronic or acute physical illnesses and were not on any medications. Severe preeclampsia was defined by the American College of Obstetricians and Gynecologists guidelines18 and included blood pressure measurements of 160 mm Hg systolic or 110 mm Hg diastolic or higher, proteinuria of 5 g or more in 24 hours, thrombocytopenia (100,000/mL or less), oliguria (500 mL or less in 24 hours), elevated liver function enzymes, intrauterine growth restriction or oligohydramnios, or seizures. After centrifugation, the plasma samples were aliquoted and stored at −20C until further use. Butylated hydroxytoluene (final concentration of 1 mmol/L, Sigma, St. Louis, MO) was added only to the samples used in the malondialdehyde assay to prevent oxidation.

Malondialdehyde, a breakdown product of lipid peroxides, was measured as previously described.19 In the presence of heat and acid, malondialdehyde reacts with thiobarbituric acid to form a red pigment having a peak wavelength of 530 nm. All reagents for this assay were purchased from Sigma, St. Louis, MO. Malondialdehyde standards were prepared by hydrolysis of 1,1,3,3‐tetramethhoxypropane. Samples were mixed with 0.2 mol/L of phosphoric acid, 5 mmol/L of butylated hydroxytoluene, and 0.11 mol/L of thiobarbituric acid. Additional butylated hydroxytoluene (final concentration 5 mmol/L) was added to the plasma samples to prevent lipid peroxidation reactions during the heating step. The mixture was incubated at 90C for 45 minutes, briefly put on ice, and then allowed to cool to room temperature. Malondialdehyde was extracted with n‐butanol, and saturated sodium chloride was added to help phase separation. After centrifugation, the organic phase was transferred to a flat‐bottom 96‐well plate (Costar Corp., Cambridge, MA). Absorption was measured by a 96‐well plate reader (Spectra, Microplate Autoreader, Tecan, NC) at 530 nm and at 570 nm to correct for background absorption. Malondialdehyde levels were calculated using the difference in absorption at the two wavelengths. The within‐assay variation was 7.4%, and all samples were run in the same assay to eliminate between‐assay variation. Significance calculations were performed with a two‐tailed Student t test.

Human umbilical vein endothelial cells were isolated from fresh term umbilical cords as previously described.20 Briefly, both ends of the umbilical cord were cannulated with one‐way stopcocks, and the lumen was perfused with phosphate‐buffered saline. The lumen then was filled with phosphate‐buffered saline containing 0.1% collagenase (Clostridium histolyticum, Type I, Sigma) and incubated at 37C for 15 minutes. The collagenase solution was flushed into conical tubes using an equal volume of Hanks balanced salt solution, and the endothelial cells were pelleted by centrifugation at 200 g for 5 minutes. The endothelial cells were resuspended in F‐12K (American Type Culture Collection) containing 10% fetal bovine serum (Life Technologies), 20 μg/mL of endothelial cell growth supplement (Sigma, St. Louis, MO), 90 μg/mL of heparin (Sigma), antibiotic/antimycotic solution (100 U/mL of penicillin, 100 μg/mL of streptomycin, and 25 μg/mL of amphotericin B, Life Technologies), and plated into 0.2% gelatin‐coated (Sigma) 25 cm2 flasks (Corning Inc., Corning, NY). Experiments were performed on cells in the sixth passage. Cells were previously identified as endothelial cells by morphology and factor VIII staining.20

To determine the effect of preeclamptic plasma and vitamin E on endothelial cell monocyte chemoattractant protein‐1 and interleukin‐8 production, human umbilical vein endothelial cells were plated into gelatin‐coated 24‐well plates and grown to near confluence, then were treated with 5% plasma from normal (n = 12) or severe preeclamptic patients (n = 12) with or without 50 μmol/L of vitamin E for 48 or 72 hours. The condition media were collected, centrifuged for 10 minutes, and stored at −70C until further use.

Monocyte chemoattractant protein‐1, interleukin‐8, and tumor necrosis factor‐α were measured in plasma and human umbilical vein endothelial cells conditioned media using commercially available enzyme‐linked immunosorbent assays (ELISAs) (OptEIA human monocyte chemoattractant protein‐1, interleukin‐8, tumor necrosis factor‐α set, Pharmingen, San Diego, CA) according to the manufacturer's recommendations. Color development of the ELISAs used tetramethylbenzidine as the substrate, and the optical density of the plate wells was determined at 450 nm using a Spectra, Microplate Autoreader. The sensitivity and range of the monocyte chemoattractant protein‐1 and tumor necrosis factor‐α ELISAs were from 31.2 to 2000 pg/mL and the interleukin‐8 ELISAs 3.1 to 200 pg/mL, respectively. To validate the assays, samples were either serially diluted, or known amounts of the monocyte chemoattractant protein‐1, interleukin‐8, or tumor necrosis factor‐α standard were added and compared with the standard curve to demonstrate appropriate parallelism.

Statistical analysis was performed using a SigmaStat (SPSS Inc., Chicago, IL) statistical program. For the studies concerning human umbilical vein endothelial cells production of monocyte chemoattractant protein‐1 and interleukin‐8, a two‐tailed Student t test was used, and for the effect of vitamin E on human umbilical vein endothelial cells monocyte chemoattractant protein‐1 and interleukin‐8 production, a paired Student t test was used only after first determining normality of the data by the Kolmogorov‐Smirnov test and equal variance between groups by the Levene Median test. Because of the large variation in plasma monocyte chemoattractant protein‐1 and interleukin‐8 levels, the Mann‐Whitney rank‐sum test was used due to the normality testing failure by the Kolmogorov‐Smirnov test, and the data were represented by a box plot, which demonstrates the median, 25th/75th percentile (box), 10th/90th percentile (whisker), and 5th/95th percentile (outlying point).

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RESULTS

The demographics of pregnancies with and without preeclampsia were compared and are presented in Table 1. As expected, compared with a normal pregnancy, those affected by preeclampsia demonstrated a significantly higher systolic blood pressure (164 ± 15 versus 123 ± 16 mm Hg, mean ± standard error of the mean, P < .001) and a significantly higher diastolic blood pressure (99 ± 12 versus 68 ± 8 mm Hg, mean ± standard error of the mean, P < .001). Women with preeclampsia also had a higher mean body weight when compared with normal controls (99 ± 23 versus 75 ± 13 kg, mean ± standard error of the mean, P < .01). Although maternal age, gestational age, gravidity, parity, birth weight, and placenta weight were noticeably lower in the pregnancies with preeclampsia compared with normal pregnancies, these differences did not reach statistical significance. Of the patients who developed preeclampsia, two had chronic hypertension, one had gestational diabetes, and one had a prior history of preeclampsia. The other six preeclamptic patients had no other preexisting or concurrent medical problems. Nine of the 12 patients were classified as having severe preeclampsia based on blood pressure (systolic greater than 160 mm Hg or diastolic greater than 110 mm Hg), three patients based on elevated hepatic enzymes and thrombocytopenia (hemolysis, elevated liver enzymes, low platelets syndrome), and one patient based on blood pressure in addition to intrauterine growth restriction and oligohydramnios. Although all patients had severe preeclampsia at the time of study, the presence of chronic hypertension, gestational diabetes, hemolysis, elevated liver enzymes, low platelets, and intrauterine growth restriction in certain individuals indicates that some of these patients may have different underlying disease states contributing to their diagnosis.

Table 1
Table 1
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Numerous studies have established that circulating levels of lipid peroxides are elevated in preeclampsia.6 As expected, plasma samples from severe preeclamptic patients showed a 4.5‐fold higher concentration of malondialdehyde compared with normal pregnant patients samples. The significantly higher malondialdehyde (6.12 versus 1.36 μmol/L, P < .001) concentration indicates increased levels of lipid peroxides in the plasma samples from preeclamptic patients used in these in vitro studies.

Serum levels of tumor necrosis factor‐α have been reported to be elevated in preeclampsia.21 Because tumor necrosis factor‐α can induce monocyte chemoattractant protein‐1 and interleukin‐8 production in vascular endothelial cells, we measured levels of tumor necrosis factor‐α in the normal and preeclamptic women plasma samples used in these studies. None of the samples from any of the patients in this study were found to have detectable levels of tumor necrosis factor‐α. One explanation for these findings is that the lower detection limit of the tumor necrosis factor‐α ELISA used in this study was 31.2 pg/mL, whereas other studies used more sensitive assays and report tumor necrosis factor‐α levels in the range of 1–10 pg/mL in women with preeclampsia.21,22 The initial characterization of our human umbilical vein endothelial cells model system showed that less than 10 pg/mL of tumor necrosis factor‐α did not stimulate monocyte chemoattractant protein‐1 or interleukin‐8 production making any effect of low levels of tumor necrosis factor‐α in the plasma samples unlikely (data not shown).

Previous studies in our laboratory demonstrated that plasma from preeclamptic women induces human umbilical vein endothelial cell intracellular adhesion molecule‐1 expression.14 Because both monocyte chemoattractant protein‐1 and interleukin‐8 expression have been shown to be upregulated by oxidative stress and lipid peroxides, we tested the hypothesis that preeclamptic plasma would also stimulate the production of monocyte chemoattractant protein‐1 and interleukin‐8. In human umbilical vein endothelial cells treated with 5% plasma from normal or severe preeclamptic patients, the conditioned medium was found to contain 2.3‐fold higher levels of monocyte chemoattractant protein‐1 (P < .001) and 1.5‐fold higher levels of interleukin‐8 (P < .005) compared with normal plasma‐treated human umbilical vein endothelial cells (Figure 1).

Figure 1
Figure 1
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To determine if the antioxidant vitamin E could inhibit the increased production of endothelial cell monocyte chemoattractant protein‐1 and interleukin‐8 in the above studies, human umbilical vein endothelial cells were cultured in the presence of 5% preeclamptic or normal pregnant plasma with 50 μmol/L of vitamin E or vehicle as a control. In human umbilical vein endothelial cells treated with preeclamptic plasma, conditioned media contained ten‐fold less monocyte chemoattractant protein‐1 (P < .001) and 1.9‐fold less interleukin‐8 (P < .005) in cells that were treated with vitamin E than in the vehicle‐treated control cells (Figure 2). Vitamin E treatment did not significantly reduce (less than 5%) production of monocyte chemoattractant protein‐1 or interleukin‐8 in human umbilical vein endothelial cells treated with normal pregnant plasma. Because of limiting quantities of human umbilical vein endothelial cells‐conditioned media available in several samples, only ten subjects in the preeclamptic and normal groups were evaluated for interleukin‐8 production.

Figure 2
Figure 2
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Our initial findings that preeclamptic plasma induced the production of monocyte chemoattractant protein‐1 and interleukin‐8 in human umbilical vein endothelial cells prompted us to determine if women with preeclampsia had higher circulating levels of monocyte chemoattractant protein‐1 and interleukin‐8 compared with normal pregnant women. Women with preeclampsia had 1.5‐fold higher plasma levels of monocyte chemoattractant protein‐1 (P < .03) and 2.5‐fold higher levels of interleukin‐8 (P < .05) compared with women with normal pregnancies (Figure 3). These findings suggest that endothelial activation resulting in the increased production of chemokines is present in women with preeclampsia.

Figure 3
Figure 3
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DISCUSSION

Preeclampsia is a systemic disease characterized by hypertension, proteinuria, and edema, which are thought to be the result of diffuse endothelial activation and dysfunction. Increased oxidative stress has been proposed as a factor that can lead to endothelial cell dysfunction in preeclampsia. During normal pregnancy, the placenta produces significant quantities of reactive oxygen species and lipid peroxides.23 In women with dyslipidemia and increased lipid peroxides, the ability of the antioxidant systems to neutralize placental lipid peroxides is exceeded, and a pathologic state of oxidative stress develops. Many of the same risk factors for preeclampsia including hyperlipidemia, hypertension, and obesity are also found in individuals who develop atherosclerotic vascular disease.2,3,24 The histologic presence of lipid laden macrophages in decidual arterioles, termed “acute atherosis” has led a number of investigators to draw parallels between the pathophysiology of the atherosclerosis disease process with that of preeclampsia.10,25

A current model for the pathogenesis of monocyte recruitment to atherosclerotic vascular lesions involves the activation of vascular endothelium by oxidized lipids.26 In this model, oxidized lipids promote activation of nuclear transcription factor‐κB in endothelial cells resulting in the upregulation of cell surface adhesion molecules such as intracellular adhesion molecule‐1, and monocyte chemokines including monocyte chemoattractant protein‐1 and interleukin‐8. The increased endothelial cell intracellular adhesion molecule‐1, monocyte chemoattractant protein‐1, and interleukin‐8 expression result in the adherence of circulating monocytes to the vascular endothelium, with subsequent migration of the adherent monocytes into the vascular wall.

A significant finding of this study is that plasma from preeclamptic women stimulates the production of monocyte chemoattractant protein‐1 and interleukin‐8 in vascular endothelial cells. One potential mechanism by which preeclamptic plasma increased human umbilical vein endothelial cells monocyte chemoattractant protein‐1 and interleukin‐8 production is through lipid peroxide activation of nuclear transcription factor‐κB. Consistent with previous reports, the preeclamptic plasma samples used in the current in vitro studies had significantly higher levels of lipid peroxides compared with plasma samples from normal pregnant women.6,7 Although several studies have found increased circulating tumor necrosis factor‐α in women with preeclampsia, there were no significant differences in tumor necrosis factor‐α levels found in this study, possibly because of the lower sensitivity of the assay used in this study. It is also possible that other unidentified factors present in preeclamptic plasma result in the increased levels of lipid peroxides and also stimulate endothelial cell monocyte chemoattractant protein‐1 and interleukin‐8 production.

Increased monocyte chemoattractant protein‐1 and interleukin‐8 production by human umbilical vein endothelial cells exposed to preeclamptic plasma was inhibited with vitamin E, suggesting elevated lipid peroxides and oxidative stress, or perhaps other inflammatory cytokines,27 were responsible for the increased expression of these chemokines. Consistent with these findings is a recent report from our laboratory that elevated lipid peroxides in preeclamptic plasma activate nuclear transcription factor‐κB and upregulate intracellular adhesion molecule‐1 expression in human umbilical vein endothelial cells, a process that could be inhibited with vitamin E or N‐acetyl‐cysteine.14 Taken together, these findings support the hypothesis that the pathogenic mechanisms involving monocyte recruitment in “acute atherosis” associated with preeclampsia are similar to the mechanisms in monocyte recruitment to arteriosclerotic vascular lesions. These findings also suggest that models of lipid peroxide‐induced endothelial activation in atherosclerosis may be useful in the study of endothelial activation in preeclampsia.

Consistent with our in vitro findings that preeclamptic plasma stimulates endothelial production of monocyte chemoattractant protein‐1 and interleukin‐8, we found that circulating plasma levels of these chemokines were elevated in preeclamptic women compared with normal pregnant women. Although activated vascular endothelial cells are probably responsible, in part, for increased circulating monocyte chemoattractant protein‐1 and interleukin‐8 levels in preeclamptic women, other potential sources for these chemokines during pregnancy are the placenta, maternal decidua, and circulating leukocytes.28,29 Several other diseases, associated with vascular endothelial cell abnormalities including diabetes mellitus, hemolytic uremic syndrome, and vasculitis or glomerulonephritis with autoimmune disease, are also associated with elevated circulating monocyte chemoattractant protein‐1 or interleukin‐8.30–36 The presence of elevated plasma levels of monocyte chemoattractant protein‐1 and interleukin‐8 in our preeclamptic patients also suggests the possibility that these chemokines might serve as potential clinical markers for preeclampsia. However, given the heterogeneous nature of patients with severe preeclampsia and the relatively small number of patients enrolled in the current study, caution must be advised in extrapolating these findings to all patients with preeclampsia.

A recent study by Chappell et al suggests that supplementation with vitamins E and C of pregnant women at high risk for preeclampsia was beneficial in the prevention of preeclampsia.37 In this study, women at risk for preeclampsia received daily supplementation with 400 IU of vitamin E and 1000 mg of vitamin C beginning midgestation. Treatment with vitamins E and C resulted in a significant decrease in the incidence of preeclampsia (8%) compared with the placebo group (17%). The rationale for using vitamins E and C in this study and the likely explanation of the observed beneficial effect was to decrease oxidative stress. The present study provides a potential molecular mechanism for the beneficial clinical effects of antioxidant treatment for the prevention of preeclampsia. According to our data, plasma from women with preeclampsia stimulates monocyte chemoattractant protein‐1 and interleukin‐8 production in endothelial cells in vitro. Furthermore, the addition of 50 μmol/L of vitamin E, a dose comparable with serum levels resulting from taking 400 IU of vitamin E orally, significantly decreased monocyte chemoattractant protein‐1 and interleukin‐8 production in endothelial cells cultured with preeclamptic plasma. Taken together, these studies support the hypothesis that, in part, the beneficial effect of antioxidant therapy in the prevention of preeclampsia is through the inhibition of vascular endothelial cell activation.

In summary, severe preeclampsia is associated with elevated levels of circulating lipid peroxides, monocyte chemoattractant protein‐1, and interleukin‐8. Plasma from preeclamptic women stimulates the production of monocyte chemoattractant protein‐1 and interleukin‐8 in human umbilical vein endothelial cells. In addition, antioxidant treatment with vitamin E of human umbilical vein endothelial cells exposed to preeclamptic plasma inhibits monocyte chemoattractant protein‐1 and interleukin‐8 production. These findings suggest that circulating factors in the plasma of women with preeclampsia stimulates endothelial cell monocyte chemoattractant protein‐1 and interleukin‐8 production, and although not directly examined in this study, may increase monocyte adherence to the vascular endothelium.

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© 2002 The American College of Obstetricians and Gynecologists

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