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(Hypertension. 2004;44:708.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Short- and Long-Term Changes in Plasma Inflammatory Markers Associated With Preeclampsia

Dilys J. Freeman; Frances McManus; Elizabeth Ann Brown; Lynne Cherry; John Norrie; Jane E. Ramsay; Peter Clark; Isobel D. Walker; Naveed Sattar; Ian A. Greer

From the Division of Developmental Medicine (D.J.F., F.M., E.A.B., J.E.R., N.S., I.A.G.) and Department of Pathological Biochemistry (L.C., N.S.), University of Glasgow; Centre for Healthcare Randomised Trials (J.N.), Health Services Research Unit, Aberdeen University; Department of Transfusion Medicine (P.C.), Ninewells Hospital, Dundee; and Department of Haematology (I.D.W.), Royal Infirmary, Glasgow, United Kingdom.

Correspondence to Dr Dilys Freeman, Division of Developmental Medicine, Third Floor Queen Elizabeth Building, Royal Infirmary, 10 Alexandra Parade, Glasgow, G31 2ER, UK. E-mail d.freeman{at}clinmed.gla.ac.uk

	Abstract

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Preeclampsia is characterized by hypertension, dyslipidemia, and increased systemic inflammatory response and has been associated with an increased maternal risk of cardiovascular disease later in life. Low-grade chronic inflammation is a risk factor for cardiovascular disease. This study examined changes in inflammatory markers prospectively during pregnancy, the current inflammatory status of women who had a pregnancy complicated by preeclampsia 20 years previously against matched controls, and the association between inflammatory genes and risk of preeclampsia in a case (n=106) control (n=212) study. In control pregnancies (n=34), mean interleukin-10 (IL-10) levels increased 38% (P=0.012) and tumor necrosis factor- (TNF-) by 33% (P=0.024) between the first and third trimesters. The mean preeclampsia group IL-10 and TNF- rose by 43% (P=0.013 and P=0.0065, respectively) from the first to the third trimester. In women with preeclampsia only, plasma IL-6 increased from the first to the third trimester (1.66 [2.04] to 2.94 [2.47] pg/mL; P=0.0004). Twenty years after the index pregnancy, women who had had preeclampsia demonstrated significantly higher IL-6 to IL-10 ratio (3.96 [6.07] versus 2.12 [1.89]; P=0.034) compared with a healthy index pregnancy 20 years previously, that persisted after adjustment for smoking and current body mass index. The IL-1ß (C-511T), IL-6 (G-174C), TNF- (G-308A), E-selectin (S128R), intercellular adhesion molecule-1 (K469E), and C-reactive protein (C1059G) polymorphisms were not associated with risk of developing preeclampsia. In conclusion, preeclampsia is associated with short- and long-term changes in inflammatory status.

Key Words: preeclampsia • polymorphism • cardiovascular diseases • inflammation

	Introduction

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Preeclampsia (PE) is a disorder peculiar to pregnancy¹ and a major cause of maternal death and damage to the developing baby. It is characterized by widespread endothelial dysfunction throughout the maternal circulation resulting in hypertension attributable to vasoconstriction, proteinuria attributable to glomerular damage, and edema attributable to an increase in vascular permeability. It has now been shown that PE may herald heart disease later in life for the mother.^2,3

The specific factors initiating endothelial damage in PE are unknown, although activation of the coagulation system, platelets, and neutrophils are implicated.¹ Normal pregnancy is associated with activation of peripheral blood leukocytes, a response more marked in women with PE.⁴ Inflammatory cells are activated in PE and localized to the site of vascular injury.⁵ This white cell activation is associated with higher levels of proinflammatory molecules, cytokines, and adhesion molecules. Plasma levels of interleukin-6 (IL-6) and tumor necrosis factor- (TNF-) have been shown by ourselves⁶ and others^7,8 to be raised in PE. It has been suggested that PE is attributable to an excessive maternal inflammatory response to pregnancy secondary to a combination of placental factors and maternal factors related to phenotype and genotype.⁹ This inflammatory response contributes to the wider syndrome of endothelial dysfunction and thrombotic and metabolic disturbances seen in PE.

The parallels between metabolic disturbances in PE and cardiovascular disease (CVD) are striking and may explain the risk of future CVD associated with PE.¹⁰ Recently, there has been recognition of the role of inflammation in atherosclerosis.¹¹ Markers of inflammation independently predict CVD events.¹² Another common risk factor shared by PE and CVD is obesity.¹³ Adipose tissue is now recognized as an endocrine organ that secretes a number of active substances including proinflammatory cytokines.¹⁴ Adipose tissue produces IL-6 and TNF-, and these cytokines might contribute to insulin resistance and the resulting dyslipidemia, both features of PE. Variation in genes coding for inflammatory cytokines might be associated with risk of inflammatory disease and atherosclerosis.^15–18 However, studies assessing the impact of variation at inflammatory genes on risk of PE are sparse.^19–22

The aim of this study was to compare baseline and, prospectively, short-term pregnancy-induced changes in plasma inflammatory markers in women who experienced healthy pregnancies with those whose pregnancy was complicated by PE. In addition, we compared plasma inflammatory markers between women with a healthy pregnancy to those with pregnancy complicated by PE an average of 20 years earlier. Finally, we studied whether variation at genes coding for inflammatory markers is predictive of PE.

	Methods

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Patient Populations
All patient samples were collected from the same West of Scotland population attending the Princess Royal Maternity Unit at Glasgow Royal Infirmary. Ethical approval was received from the North Glasgow University Hospital National Health Service (NHS) trust research ethics committee, and all women gave informed consent. Women with PE were identified according to criteria defined by the International Society for the Study of Hypertension in Pregnancy (ISSHP) (ie, diastolic blood pressure >110 mm Hg on 1 occasion or >90 mm Hg during repeated readings, with proteinuria 0.3 g for 24 hours, or 2+ proteinuria during dipstick testing, without renal disease or infection).

Study 1
Study 1 used samples collected for the Glasgow Outcome, Activated protein-C resistance, and Lipid (GOAL) Pregnancy Study.²³ Baseline plasma samples were available from 45 women who subsequently developed PE and from 45 age- and parity-matched controls who experienced no adverse pregnancy outcome. In a subset (n=34 per group), first and third trimester plasma samples were available.

Study 2
Primigravidae delivering between 1975 and 1985 with proteinuric PE in line with the ISSHP criteria and matched controls were identified from medical records as described previously.²⁴

Study 3
By combining available samples of blood cell pellets from studies 1 and 2, plus an additional 21 PE women from study 1 who had blood cells available for DNA extraction but no plasma samples, 106 women with a history of PE from the same West of Scotland population attending the same maternity hospital were identified, each matched for age (±2 years) and parity (0, 1, >1) with 2 control samples.

Biochemical Assays
Plasma IL-6, IL-10, soluble (s) intercellular adhesion molecule-1 (ICAM-1), s vascular cell adhesion molecule-1 (VCAM-1), and TNF- were measured in citrated plasma stored at –80°C using high-sensitivity commercial ELISA kits (R&D Systems). C-Reactive protein (CRP) was measured using a high-sensitivity, 2-site enzyme-linked immunoassay.²⁵

Polymorphism Detection
DNA was extracted from packed blood cells stored at –80°C.²⁶ Polymorphisms were detected by polymerase chain reaction amplification and digestion with the appropriate restriction enzyme. Methods were as described: CRP G1059C,²⁷ E-selectin S128R,²⁸ ICAM-1 K469E,²⁹ IL-1ß C-511T,³⁰ IL-6 G-174C, ³¹ and TNF- G-308A.³⁰

Statistical Analysis
Baseline (first trimester) characteristics were tabulated and compared between the PE and control groups using 2-sample t tests for continuous data or ² tests (or Fisher exact tests) for categorical data. For some of the skewed continuous variates, data were log transformed. For IL-10, which had some zeroes, the Wilcoxon rank sum test was used. For the ratio of IL-6 to IL-10, a zero IL-10 was ranked highest, and a Wilcoxon rank sum test was used. Within a group (either PE or controls), changes at third trimester over first trimester (baseline) were compared using paired 1-sample t tests, and then these differences between trimesters were compared between groups using 2-sample t tests. Throughout, all the estimated differences were then adjusted for important covariates, such as smoking, body mass index (BMI), gestational age, and menopausal status using normal linear models. The influence of the various genotypes was investigated using conditional logistic regression, with strata of age crossed with parity, with an additional term to adjust for study. Odds ratios with 95% confidence intervals and associated P values are reported. All analyses were performed in SAS 8.2 for Windows. No adjustments have been made for multiple comparisons.

	Results

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Study 1: Baseline Plasma Inflammatory Markers
Baseline characteristics for study 1 are shown in Table 1. There were no significant differences in booking BMI, Carstairs social deprivation category,³² twin pregnancies, and gestational age at sampling. As expected, the PE group had a trend toward higher baseline diastolic blood pressure, had significantly fewer smokers (P=0.021), and delivered babies of lower birth weight centile (mean [SD] control 52.3 [31.3] versus PE 33.2 [26.5]; P=0.0026). There were no significant differences in baseline plasma IL-10, IL-6/IL-10 ratio, sICAM-1, sVCAM-1, CRP, or TNF- levels between control women and women who subsequently developed PE. Women with a PE pregnancy had a tendency to higher plasma IL-6 levels than age- and parity-matched healthy pregnancy women (control 1.19 [0.70] versus PE 1.58 [1.79] pg/mL; P=0.051). This difference in IL-6 was independent of smoking (P=0.052) but was attenuated on adjusting for smoking and booking BMI (least squares mean [SEM] in controls 1.20 [0.23] versus PE 1.56 [0.28] pg/mL; P=0.26).

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics for Study 1

Study 1: Third Trimester Inflammatory Markers
Third trimester inflammatory markers were available in a subset of 34 individuals from study 1 (Table 2). There were significantly higher levels of IL-6 (controls 1.47 [0.88] versus PE 2.94 [2.47]; P<0.0001) and CRP (controls 3.34 [3.40] versus PE 5.84 [5.38]; P=0.0091) in third trimester PE women compared with control women. The difference in IL-6 was independent of booking BMI, smoking, and gestational age at third trimester combined (P=0.0052). However, the difference in CRP was independent of smoking (P=0.0062) but is attenuated by booking BMI plus smoking (P=0.063) and further by booking BMI, smoking, and gestational age at third trimester (P=0.14).

View this table: [in this window] [in a new window]   TABLE 2. First and Third Trimester Inflammatory Markers in Study 1

Study 1: First to Third Trimester Changes in Inflammatory Markers
First and third trimester samples were available for plasma inflammatory markers in 34 individuals (Table 2). In PE and control groups, plasma IL-10 and TNF- levels were increased significantly between first and third trimesters. However, these differences were not independent of smoking and booking BMI. Plasma IL-6 levels were significantly increased between the first and third trimester in the PE group but not the control group, and this difference was unaffected by smoking (P=0.0012) but was attenuated by the inclusion of BMI (P=0.046). When the mean change in inflammatory markers between first and third trimester was compared (Table 3), plasma IL-6 showed a significantly larger change in PE (77%) compared with controls (21%) (control mean change 0.25 [1.14] versus PE 1.29 [1.91] pg/mL; P=0.0091). This difference in T1 to T3 IL-6 was independent of smoking (adjusted P=0.0071) but not when additionally adjusting for BMI (P=0.20).

View this table: [in this window] [in a new window]   TABLE 3. Mean Change (SD) in First Trimester (T1) to Third Trimester (T3) Inflammatory Markers in Study 1

Study 2: Inflammatory Markers 20 Years After Pregnancy
Study 2 characteristics are shown in Table 4. Cases and controls were selected to match, as a group, for current age and BMI. All women at index pregnancy were primigravid. PE women at index pregnancy had significantly higher BMI, lower birth weight centile, and lower gestation at delivery. At recall, there were no significant differences in parity and smoking between the control and PE groups. Although more PE women were in menopause at recall, this was not a significant difference. There was a significantly higher IL-6/IL-10 ratio, an index of proinflammatory cytokine (IL-6) status to anti-inflammatory cytokine (IL-10) status, in the PE women compared with matched controls (PE 3.96 [6.07] versus control 2.12 [1.89]; P=0.034), independent of smoking, current BMI, and menopause status (P=0.03). Plasma sICAM-1 and sVCAM-1 were also higher in PE women, as we have described previously,²⁴ differences that were also independent of smoking, current BMI, and menopause status.

View this table: [in this window] [in a new window]   TABLE 4. Baseline Characteristics for Study 2

Study 3: Genetic Predictors of PE
For study 3 characteristics, please see supplemental Table I, available online at http://www.hypertensionaha.org. Cases and controls were matched for age and parity. PE cases had higher BMI and fewer smokers than the controls. Birth weight centile was significantly lower in the PE women, and there was a greater incidence of twin pregnancies in this group. The rare allele frequencies for CRP G1059C, E-selectin S128R, ICAM-1 K469E, IL-1ß C-511T, IL-6 G-174C, and TNF-G-308A polymorphisms were 0.06, 0.08, 0.42, 0.36, 0.41, and 0.22, respectively. Genotype frequencies in the total group, cases, and controls were in Hardy-Weinberg equilibrium for each of the polymorphisms and are shown in Table 5. There was no significant association between any inflammatory gene polymorphisms studied and risk of developing PE.

View this table: [in this window] [in a new window]   TABLE 5. Genotype Frequencies of Polymorphisms at Inflammatory Genes in Cases and Controls; Univariate Analysis

	Discussion

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In our prospective study, baseline IL-6 levels had a tendency to be higher in women who subsequently develop PE. However, this was not independent of BMI and may reflect the role of BMI as a risk factor for PE. In control and PE pregnant women, plasma IL-10 and TNF- increased from first to third trimester and may represent the normal inflammatory response of pregnancy with changes in proinflammatory and anti-inflammatory markers. These changes were no longer apparent after accounting for smoking habit and BMI, and thus the degree of inflammatory response to the physiological stress of pregnancy may be influenced by maternal adiposity and smoking status. Interestingly, plasma IL-6 levels were only increased during pregnancy in women who developed PE, and this increase, although attenuated, persisted after correction for booking BMI, suggesting that increases in IL-6 may be specific to PE and are not entirely determined by maternal adiposity. Thus, inflammatory pathways involving IL-6 may be involved in the etiology of PE in keeping with previous reports from cross-sectional studies. It is possible that women with other related disorders of pregnancy such as pregnancy-induced hypertension, diabetes, and intrauterine growth restriction may also show increases in plasma IL-6. Further studies should be performed in these groups to exclude this possibility.

In other prospective studies, first trimester TNF- was significantly higher in women who subsequently developed PE compared with those who did not.^33,34 However, these studies did not account for BMI. Djurovic et al³⁵ found no differences in IL-6 at 18-week gestation between women who subsequently developed PE and healthy control women when BMI was accounted for. This may suggest that an increase in IL-6 occurs later than this gestation. Many, although not all, studies have identified higher third trimester plasma levels of IL-6 and TNF- in PE women. However, only 1 study has accounted for the influence of BMI³⁶ and did confirm raised levels of these cytokines. In that study, a significant correlation between maternal serum leptin and TNF- concentration was found underlining the association between fat mass and inflammatory cytokine production. Third trimester plasma IL-10 levels are reported as higher³⁷ and lower³⁸ in PE compared with control pregnancies, although in both studies, BMI was not accounted for, and in the latter study, it is not clear that cases and controls were matched for gestational age at sampling. Thus, because maternal adipose tissue may contribute to plasma levels of TNF- and IL-10, and because plasma TNF- and IL-10 increase in normal pregnancy, failure of other studies to account for BMI and gestational age at sampling may explain differences between studies.

Our data confirm those of other groups that observed higher IL-6 at third trimester in PE^6–8,36 but not when BMI was taken into account.³⁵ The source of the IL-6 is important because these data suggest that total obesity alone does not fully explain these findings. Plasma IL-6 in pregnancy may be derived from adipose tissue (and adipose mass can be different in women of similar BMI), placenta, and circulating lymphocytes. Other researchers have been unable to identify increased IL-6 production by the placenta in PE.^39,40 Endothelial cells⁴¹ have been demonstrated to have increased IL-6 production in severe PE. Another possibility is that adipose tissue mass per se is not important, rather adipose tissue functionality. It is possible that PE women have much more "active" adipose tissue (eg, greater lipolytic rates leading to increased plasma free fatty acid concentrations and greater synthesis and secretion of adipokines). Maternal adipose tissue functionality in PE has not been studied. Correcting for the influence of smoking increases the disparity between control and PE women. This is attributable to the higher number of smoking individuals in the control group allied to the known link between smoking and higher background level of inflammatory markers. It is unlikely that IL-6 is responsible for the entire maternal metabolic syndrome of PE, but it could accentuate aspects of the response (eg, insulin resistance⁴² and endothelial dysfunction⁴³). Establishing which tissue(s) contributes to the increase in plasma IL-6 might help address some of these issues.

The retrospective study assessing inflammatory markers in women 20 years after the index pregnancy investigated whether short-term inflammatory changes seen during pregnancy are retained later in life. There was a trend toward decreased IL-10, an anti-inflammatory cytokine, in women with a history of PE and a significantly higher IL-6 to IL-10 ratio that was independent of smoking, current BMI, and menopause status. Thus, the higher inflammatory status of women with a history of PE does not merely reflect a higher BMI.

Our group has shown that sICAM-1 and sVCAM-1 were raised in women with a history of PE 20 years previously,²⁴ and the data are re-presented in Table 4. These inflammatory markers are, to some degree, thought to reflect endothelial dysfunction. Thus, their elevation in women with a history of PE may indicate a greater degree of endothelial dysfunction in these women. It is noteworthy that although the endothelial function markers, sICAM-1 and sVCAM-1, were raised in women with a previous history of PE, these markers were not elevated during pregnancy in PE. It is possible that the acute inflammatory response seen during pregnancy in PE indicates a woman’s innate susceptibility to inflammation but is not sufficient to provoke all the endothelial changes associated with chronic exposure to vascular risk factors over a number years. Our group has reported that PE women have significantly impaired endothelial function compared with controls.⁴⁴ ICAM-1 and VCAM-1 are upregulated in atherosclerosis and may act as markers for the disease. However, evidence from knockout mice indicates that VCAM-1 plays a dominant role in the initiation of atherosclerosis and is important for the disease pathway.⁴⁵ The raised sVCAM-1 levels, IL-6/IL-10 ratio, and endothelial dysfunction in combination with a higher level of inflammatory response seen in subjects with PE in our study would help explain why women with a history of PE are at increased risk of CVD. Thus, PE and CVD share common proinflammatory risk factors.

In this study, we were unable to find any significant contribution of variation at CRP, E-selection, ICAM-1, IL-ß, IL-6, or TNF- genes to risk of PE in this West of Scotland population despite their contribution to other inflammatory disease.^15–18 The current study was powered to detect a 2-fold increase in risk and would not have identified any smaller increases. Other studies have found contributions of TNF- to PE,^19–21 but these observations have not been confirmed by others,^22,46 including a large family study.⁴⁷ PE is a multifactorial disorder with an imprecise definition, and it likely has a complex and varied etiology with interaction between placental factors and maternal phenotypes and genotype being responsible for the clinical expression of this condition. Many genes, maternal and fetal, interacting with each other and a variety of environmental stimuli may therefore contribute to disease severity and outcome. Until large, well-defined PE populations are available for study, it is unlikely that genetic variants that consistently and significantly contribute to disease will be found.

Perspectives
This study suggests that susceptibility to inflammation might be a common underlying risk factor for PE and CVD. It will be important to establish whether susceptibility to inflammation is specific to PE or underlies other common disorders of pregnancy also linked to future CVD such as intrauterine growth restriction and preterm delivery. The mechanism for this inflammatory susceptibility is unknown and could be attributable to a generalized upregulation of a number of inflammatory processes or could be a specific overactivity of a particular tissue such as adipose tissue. An understanding of the genetic and metabolic mechanisms involved may inform strategies for identification and intervention in individuals at risk.

	Acknowledgments

 
Tenovus Scotland (grant reference S00/9) and the University of Glasgow Medical Research Funds Committee are gratefully acknowledged for their support.

Received May 14, 2004; first decision June 8, 2004; accepted August 24, 2004.

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