OBJECTIVE

Inflammation and endothelial dysfunction have been associated with the immunobiology of preeclampsia (PE), a significant cause of adverse pregnancy outcomes. The prevalence of PE is elevated several fold in the presence of maternal type 1 diabetes mellitus (T1DM). Although cross-sectional studies of pregnancies among women without diabetes have shown altered inflammatory markers in the presence of PE, longitudinal studies of diabetic women are lacking. In maternal serum samples, we examined the temporal associations of markers of inflammation with the subsequent development of PE in women with T1DM.

RESEARCH DESIGN AND METHODS

We conducted longitudinal analyses of serum C-reactive protein (CRP), adhesion molecules, and cytokines during the first (mean ± SD, 12.2 ± 1.9 weeks), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy (visits 1–3, respectively). All study visits took place before the onset of PE. Covariates were BMI, HbA1c, age of onset, duration of diabetes, and mean arterial pressure.

RESULTS

In women with T1DM who developed PE versus those who remained normotensive, CRP tended to be higher at visits 1 (P = 0.07) and 2 (P = 0.06) and was significantly higher at visit 3 (P < 0.05); soluble E-selectin and interferon-γ–inducible protein-10 (IP-10) were significantly higher at visit 3; interleukin-1 receptor antagonist (IL-1ra) and eotaxin were higher and lower, respectively, at visit 2 (all P < 0.05). These conclusions persisted following adjustment for covariates.

CONCLUSIONS

In pregnant women with T1DM, elevated CRP, soluble E-selectin, IL-1ra, and IP-10 and lower eotaxin were associated with subsequent PE. The role of inflammatory factors as markers and potential mechanisms of the high prevalence of PE in T1DM merits further investigation.

Preeclampsia (PE), characterized by the new onset of hypertension and proteinuria after midgestation, disproportionately affects pregnancies in women with type 1 diabetes mellitus (T1DM) (1). In general, immune aberrations, mainly originating in the placenta and leading to maternal inflammation and endothelial dysfunction, have been associated with PE (2). Existing studies of maternal circulating inflammatory molecules, especially C-reactive protein (CRP), adhesion molecules, cytokines, and chemokines, in pregnancies with and without PE are mostly cross-sectional and do not address pregnancy in diabetic women. In the absence of diabetes, prospective data suggest that markers of inflammation and endothelial dysfunction, especially CRP and adhesion molecules, may serve as potential markers for increased risk of PE (3,4). Further prospective clinical investigations are needed to define the role of these inflammatory factors as markers or mechanisms for PE in the context of T1DM.

Cross-sectional studies of pregnancies affected by PE in nondiabetic women have shown altered maternal levels of CRP, adhesion molecules, and cytokines: CRP levels (5,6) and specific cytokines and chemokines, such as interleukin (IL)-1, −6, and −8; IL-1 receptor anta gonist (IL-1ra); interferon (IFN)-γ–inducible protein-10 (IP-10); and monocyte chemoattractant protein-1 (MCP-1), were significantly elevated in women with PE versus healthy pregnant and nonpregnant controls (69), whereas IL-1β, IL-4, IL-12, and IFN-γ were not different (6,7). Levels of maternal adhesion molecules, such as soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1), also have been shown to be significantly elevated in women with PE versus healthy pregnant and nonpregnant controls (6). However, these case-control studies do not address the temporal associations of CRP, cytokines, and chemokines with the development of PE. Longitudinal studies of nondiabetic pregnant women who subsequently developed PE show significant elevations in CRP before the onset of PE (3), but conflicting results were obtained concerning adhesion molecules (10,11) and cytokines (12). One longitudinal study by Clausen et al. (13) of pregnant women with T1DM showed elevated plasma VCAM-1 and ICAM-1, but not E-selectin or vonWillebrand Factor, at 11 weeks’ gestation in those who subsequently developed PE versus those who did not. No comprehensive longitudinal data have been reported in pregnancies with or without T1DM to define the levels of key inflammatory molecules (CRP, adhesion molecules, cytokines, and chemokines) in a single cohort. Such a study might provide better insight into the inflammatory milieu preceding PE.

In our prospective study of pregnancies in women with T1DM, we previously reported altered circulating antiangiogenic factors (14), antioxidant carotenoids (15), and cholesterol-rich lipoprotein particles (16) early in pregnancy in women who subsequently developed PE. In the same prospective cohort, we have now evaluated the roles of maternal CRP, adhesion molecules, and cytokines in the subsequent development of PE in women with T1DM. Our specific goal was to define the temporal course of CRP, adhesion molecules (ICAM-1, VCAM-1, E-selectin, P-selectin) and multiple markers related to inflammation and angiogenesis, including cytokines and chemokines, at three gestational “visits,” all before onset of PE. We examined differences in these variables at each individual visit (visits 1, 2, and 3) and longitudinally (visits 1–3) between women with T1DM who did versus did not subsequently develop PE. We included a small group of nondiabetic, normotensive pregnant women to define normal values and to enable a secondary comparison between “healthy” diabetic and nondiabetic women. This study does not address PE in the absence of T1DM.

Study design and participants

The participants, study design, and enrollment criteria have been described previously (14,15). Briefly, the study was conducted according to the principles of the Declaration of Helsinki and was approved by the institutional review boards of all participating institutions in Australia, Norway, and the U.S. All participants provided written informed consent. Over a 4-year period, 151 pregnant women with established T1DM and 24 nondiabetic pregnant women were recruited during their first trimester (∼12 weeks) then followed throughout the pregnancy. Clinical data and blood and urine specimens were collected at 12.2 ± 1.9, 21.6 ± 1.5, and 31.5 ± 1.7 weeks of gestation (mean ± SD; no overlap). These three visits corresponded with late first, midsecond, and early third trimesters and, in cases of PE, preceded the onset of PE. PE was defined as new-onset hypertension (>140/90 mmHg) accompanied by proteinuria (>300 mg/24 h) after 20 weeks’ gestation in a previously normotensive woman (15). The current study uses a subset of our larger cohort (14): of the original 26 women with T1DM and PE, 23 were available for the current study (3 lost as a result of sample attrition). Women without PE but who developed pregnancy-induced hypertension were excluded from the analysis. Of the original 95 normotensive diabetic women, 26 were selected matching for age, duration of diabetes, HbA1c, and parity; of these 26 women, 23 were studied (3 lost as a result of sample attrition). Twenty nondiabetic women (DM-) were included for reference values.

Laboratory measures

Serum CRP was measured by nephelometry as previously described (17). Serum adhesion molecules (soluble E-selectin [sE-Selectin], soluble P-selectin [sP-Selectin], sICAM-1, and sVCAM-1) were measured using the Quantikine human immunoassay kits (R&D Systems, Minneapolis, MN) based on the manufacturer’s protocols. Inflammatory factors in serum were measured using the Biometric multiplex assay (Bio-Rad Inc., Hercules, CA) as described previously (18). Of 22 factors related to inflammation, nine were detectable in most (≥95%) samples at two or more visits: IL-1ra, IL-8, IL-12, MCP-1, IP-10, macrophage inflammatory protein (MIP) 1-α, MIP-1β, eotaxin, and regulated upon activation normal T cell expressed and secreted (RANTES). The remaining factors were detectable in <50% of samples at one or more visits: granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-α, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-13, IL-15, IL-17, and tumor necrosis factor (TNF)-α. The intra- and interassay coefficients of variation for each of these variables was ≤10%. All assays were performed by operators blinded to sample identity.

Statistical analysis

Our primary analysis considered differences between women with T1DM who subsequently developed PE (DM PE+) versus those who remained normotensive (DM PE-). Between-group tests for CRP, adhesion molecules (sE-selectin, sP-selectin, sICAM-1, sVCAM-1) and each selected cytokine (IL-1ra, IL-8, IL-12, MCP-1, IP-10, MIP-1α, MIP-1β, eotaxin, and RANTES) were performed at each visit using general linear models with and without the following covariates: BMI, HbA1c, age at onset of diabetes, duration of diabetes, and mean arterial pressure. Covariates were selected according to baseline differences, known associations with PE, or both. Nonparametric Mann-Whitney tests were used as appropriate. Between-group tests across all visits were performed using generalized estimating equations (GEEs), which also were performed with and without covariates. Both log-transformed and untransformed values for CRP and cytokines were considered: the conclusions were unchanged by transformation. Results were expressed for illustrative purposes as means ± SDs. All tests were two-tailed, with P < 0.05 considered as significant. No adjustments were made for multiple hypothesis testing. A secondary comparison between DM PE- and DM- pregnancies, performed to discern changes attributable to diabetes, was exploratory. Statistical analyses used SPSS Statistics for Windows, version 17.0 (SPSS Inc., Chicago, IL).

Baseline (visit 1) characteristics, as shown in Table 1, showed no significant differences in age, percentage of alcohol users and smokers, pregnancy outcomes (gravida, parity, abortus), age of onset and duration of T1DM, systolic and diastolic blood pressure, microalbuminuria, and gestational age at visit 1 between the DM PE+ and DM PE- groups. However, BMI and HbA1c were significantly higher in the DM PE+ compared with the DM PE- group. Between DM- and DM PE- women, no significant differences were noted at visit 1 except HbA1c, which was significantly higher in the diabetic versus nondiabetic pregnant women.

Table 1

Baseline characteristics of 46 women with type 1 diabetes and 20 nondiabetic controls

Baseline characteristics of 46 women with type 1 diabetes and 20 nondiabetic controls
Baseline characteristics of 46 women with type 1 diabetes and 20 nondiabetic controls

Data for our main outcome measures are shown in Table 2 and Supplementary Fig. 1. Maternal serum CRP tended to be higher at visit 1 (P = 0.07) and visit 2 (P = 0.06) and was significantly higher at visit 3 in the DM PE+ versus the DM PE- group (P < 0.05). Interestingly, at visit 3 (still before onset of PE), CRP levels in the DM PE+ group were double those in the DM PE- group. GEE analyses revealed that, overall, CRP levels were higher in the DM PE+ group than in the DM PE- group throughout pregnancy (visits 1–3).

Table 2

Serum markers of inflammation in women with T1DM with and without subsequent PE and in nondiabetic pregnant controls

Serum markers of inflammation in women with T1DM with and without subsequent PE and in nondiabetic pregnant controls
Serum markers of inflammation in women with T1DM with and without subsequent PE and in nondiabetic pregnant controls
Serum markers of inflammation in women with T1DM with and without subsequent PE and in nondiabetic pregnant controls
Serum markers of inflammation in women with T1DM with and without subsequent PE and in nondiabetic pregnant controls

While maternal sE-selectin, sP-selectin, sICAM-1, and sVCAM-1 (except visit 1) were generally higher at all visits in the DM PE+ versus the DM PE- groups, only sE-selectin reached significance and only at visit 3 (P < 0.05). GEE analyses of E-selectin revealed that, overall, levels were higher in the DM PE+ versus the DM PE- group throughout pregnancy (visits 1–3), and in GEE analyses of sICAM-1, a similar trend was observed (visits 1–3; P = 0.06).

Among the serum cytokines, IL-1ra was significantly higher only at visit 2 and IP-10 was significantly higher only at visit 3, whereas eotaxin was significantly lower only at visit 2 (P < 0.05) in the DM PE+ versus the DM PE- group. No significant differences at any visit were found for IL-8, IL-12, MCP-1, MIP-α, MIP-β, and RANTES. However, GEE analyses revealed borderline overall elevation of IL-8 in the DM PE+ versus the DM PE- group throughout pregnancy (visits 1–3; P = 0.05). Levels of 13 cytokines detected in <50% samples (GM-CSF, IFN-α, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-13, IL-15, IL-17, and TNF-α) in the two diabetic groups and nondiabetic controls are shown in Supplementary Fig. 1 (graphs XV–XXVII).

All of the significant differences between the DM PE+ and DM PE- groups, as described above, persisted after covariate adjustments. Secondary analyses showed no significant differences in the serum markers at any visit in the DM- versus the DM PE- group, except that MCP-1 was lower in the DM- group at visit 3 (P < 0.05). In addition, GEE analyses revealed that, overall, MCP-1 and RANTES levels were lower in the DM- versus the DM PE- group throughout pregnancy (visits 1–3), whereas MIP-1α exhibited a similar trend (P = 0.07).

Our prospective study reveals higher serum CRP, sE-selectin, and specific cytokines (IL-1ra and IP-10) and lower eotaxin in pregnant women with T1DM who subsequently developed PE compared with those who remained normotensive. In general, serum CRP, adhesion molecules, and cytokines were higher at most visits in women with T1DM who later developed PE than in those who remained normotensive. This suggests that exacerbated maternal inflammatory responses confer susceptibility to PE. Because these significant findings persisted following adjustments for covariates, our results show independent temporal associations of these selected inflammatory mediators with PE in women with pregestational T1DM.

CRP, an acute-phase protein produced by the liver in response to proinflammatory cytokines, has been used routinely as a biomarker to monitor progression of disease and response to treatment in patients with inflammatory diseases (19). Multiple epidemiological studies provide strong evidence that CRP can serve as an independent predictor of future vascular events, including risks of hypertension, in nonpregnant populations (20,21). Maternal CRP has been positively correlated with PE in several cross-sectional and longitudinal studies of pregnancies in nondiabetic women (3,57,22,23), but no such data have been reported previously in pregnancies complicated by T1DM. Our longitudinal study shows serum CRP to be elevated during the first and second trimesters and significantly elevated during the third trimester in women with T1DM who subsequently developed PE versus those who did not. Associations between CRP and PE largely have been explained by maternal obesity and BMI in case-control and longitudinal studies of pregnancies in nondiabetic women (3,22,23). These studies also report greater risks of PE associated with maternal CRP levels of approximately ≥5.0 mg/L, corresponding to the observed levels of serum CRP in our patients with PE. In addition, following adjustment for maternal BMI, our data show that CRP remains significantly associated with PE. This independent association, even in the presence of elevated maternal BMI, might be explained by the role of pregestational T1DM in producing exaggerated maternal inflammatory responses in pregnancies in diabetic compared with nondiabetic women.

In our study, GEE analyses revealed elevated CRP throughout pregnancy in diabetic women who later developed PE versus those who remained normotensive. Interestingly, we observed minimal changes in CRP throughout pregnancy (visits 1–3) in normotensive women with T1DM. These findings are supported by previously reported data from non-PE pregnancies in women with T1DM, in which maternal CRP showed no significant overall changes with advancing pregnancy, except when stratified by glycemic control status (24). Thus, our longitudinal study shows increasing CRP with advancing pregnancy to be an indicator of enhanced maternal systemic inflammation and of risk for PE in T1DM.

Endothelial dysfunction, characterized by increased expression of adhesion molecules (sICAM-1, sVCAM-1) and members of the selectin (E and P) family, has been shown to promote endothelial adhesion and accumulation of inflammatory cells, thus initiating the development of vascular disease (25,26). Maternal levels of adhesion molecules have been associated with PE in case-control and longitudinal studies of pregnancies in nondiabetic women. However, results are conflicting: the data show elevated (6,10,11), lower (11), and/or similar (11) levels of one or more adhesion molecules to be associated with subsequent development of PE. In the context of pregnancy in women with T1DM, a single longitudinal study by Claussen et al.(13) showed elevated plasma levels of VCAM-1 and ICAM-1, but not E-selectin, at 11 weeks’ gestation in women who subsequently developed PE versus those who did not. Our longitudinal study assessed levels of adhesion molecules at three “visits” before the onset of PE and revealed significantly higher sE-selectin at visit 3 only (∼32 weeks) in women who later developed PE versus those who did not. We did not observe any significant differences in levels of sP-selectin, sICAM-1, or sVCAM-1 in association with PE. Differences between our study and that of Claussen et al. might be explained by differences in group size, timing of sample collections, and overall glycemic control. While adhesion molecules have been strongly correlated with endothelial dysfunction in nonpregnant cohorts with T1DM (27,28), their roles in the development of hypertensive complications, including PE, in pregnancies in women with T1DM remain to be defined in detail.

In the current study, GEE analyses showed no significant differences in levels of adhesion molecules throughout pregnancy in women with T1DM who later developed PE versus those who did not. However, while the change in sE-selectin was minimal throughout pregnancy in the DM PE+ group, the DM PE- group showed a decrease in sE-selectin with advancing pregnancy. In a previously reported longitudinal study in non-PE pregnancies in women with T1DM, no significant changes were noted in E-selectin and ICAM-1, whereas VCAM-1 increased significantly between 12 and 36 weeks of gestation (29). The discrepancies between this study and ours might be explained by maternal characteristics, including overall glycemic control and timing of sample collections.

Cytokines and chemokines are considered to be immunological markers and have been implicated in endothelial dysfunction and subsequent vascular abnormalities (30). While an increase in cytokines during pregnancy reflects successful implantation and placentation, an imbalance between cell-mediated immunity type 1 helper T cells (TH1) (e.g., IL-12) and allergic immunity type 2 helper T cells (TH2) (e.g., IL-4)–type cytokines has been implicated in PE (31,32). Several cytokines and chemokines have been reported to be altered in PE in cross-sectional and longitudinal studies of pregnancies in nondiabetic women (69,12). However, no data examining the associations between levels of cytokines and chemokines and the subsequent onset of PE have been reported in pregnant women with T1DM. In our prospective study, we observed significantly elevated IL-1ra and IP-10 at the midsecond and early third trimesters, respectively, before the onset of PE in the DM PE+ versus the DM PE- group. These specific cytokines have been correlated with β-cell function and progression of T1DM. As a natural antagonist to IL-1β, which is thought to contribute to β-cell destruction, IL-1ra has been identified as an anti-inflammatory cytokine (33) and has been shown to be elevated in nondiabetic women with PE (6,34,35). The increased levels of IL-1ra indirectly reflect increased activities of IL-1α and -β; both have a very short half-life and are often difficult to detect (34,35). On the other hand, IP-10 is considered a proinflammatory cytokine contributing to the progression of T1DM (36); it has been shown to be elevated in studies of PE in pregnancies of nondiabetic women (6,35). We also observed significantly lower eotaxin at the midsecond trimester in women with T1DM who subsequently developed PE compared with those who remained normotensive. Eotaxin, a less commonly measured proinflammatory cytokine in the context of PE, previously has been shown to be similar between PE and non-PE cases (9) but has not been reported in other studies of PE in pregnancies of nondiabetic women (68,12). Thus, our observation of generally lower eotaxin at all visits in women with T1DM who later developed PE, when compared with those who did not, suggests a possible role for eotaxin in PE and warrants further investigation.

Although our study provides novel evidence of the temporal associations of IL-1ra, IP-10, and eotaxin with subsequent PE in pregnancies of women with T1DM, we were not able to detect many other proinflammatory cytokines associated with PE, such as IL-6 and TNF-α (12), in the majority of our samples. Our results conform to previously reported data from pregnancies in nondiabetic women, in which several cytokines, such as GM-CSF, IFN-γ, or TNF-α, were below detection limits in maternal serum samples at one or more visits (12). Thus, individual and/or synergistic function of cytokines in the development of PE in T1DM needs to be defined further in larger studies defining effects of gestational age or differences in analytical methods.

In our study, GEE analyses showed no significant differences in levels of any cytokines with advancing pregnancy between the DM PE+ and DM PE- groups. We observed a borderline significant decrease in IL-8 with advancing pregnancy in women with T1DM who later developed PE versus those who did not. Our results conform to previously reported data in non-PE pregnancies in women with T1DM, showing no differences in levels of proinflammatory cytokines with advancing pregnancy, even when stratified by glycemic status (24).

Our secondary analyses revealed no significant changes in any of the markers of inflammation, except MCP-1, which was lower in the DM- versus the DM PE- group. These results conform to some previous studies showing no significant differences in inflammatory markers (CRP, IL-6, VCAM-1) between women with T1DM and nondiabetic women throughout pregnancy (24), but do not conform to others showing elevated CRP but not VCAM-1 in subjects with T1DM versus nondiabetic control subjects (37). Thus, inflammatory markers may be differentially modulated with advancing pregnancy in the absence versus presence of T1DM and may be related to metabolic control.

The specific limitations of our study include a small sample size, especially in the diabetic group who later developed PE; the absence of prepregnancy levels of inflammatory markers of interest; and the absence of a nondiabetic PE group. The latter was not included in our study design because it was not feasible (considering time and resources needed given the low PE case yield in nondiabetic women). We did not take multiple hypotheses testing into account, but our significant findings are biologically plausible and consistent with previously reported scientific literature describing nondiabetic pregnancies. Another possible limitation concerns analyses of cytokines, which are highly unstable molecules that are susceptible to variations in time, temperature, and handling procedures (38). Although we ensured optimal techniques at all stages of analysis, variation due to these factors might have contributed to the nondetectable levels of certain cytokines and chemokines. Similar variations in cytokine levels have been reported previously in studies of nondiabetic pregnancies, suggesting significant diversity in cytokine metabolism in physiological and complicated pregnancies (12,39).

In conclusion, our prospective study provides new details of the temporal course of maternal inflammatory markers in pregnancies complicated by T1DM with and without subsequent PE. We found that significantly higher CRP and specific adhesion molecules (sE-selectin) and cytokines (IL-1ra, IP-10) and lower eotaxin were associated with the subsequent development of PE at one or more gestational ages in women with T1DM. In general, levels of CRP, adhesion molecules, and cytokines (except eotaxin) were elevated throughout pregnancy in diabetic women who subsequently developed PE versus those who did not, suggesting that activation of systemic inflammation may be a mediator of PE in the presence of T1DM. Our findings support the conduct of larger studies to confirm the role of inflammation and to define the utility of inflammatory factors in the etiology, early screening, and development of preventive and therapeutic strategies for PE in T1DM.

T.J.L. received support through research grants from the Juvenile Diabetes Research Foundation (JDRF 1-2001-844) and Novo Nordisk. This study also was funded by National Institutes of Health (National Center for Research Resources) grants M01-RR-1070 and M01 RR-14467 to the General Clinical Research Centers at Medical University of South Carolina and University of Oklahoma Health Sciences Center, respectively. Support from Novo Nordisk enabled the participation of the Barbara Davis Diabetes Center for Childhood Diabetes at the University of Colorado. No other potential conflicts of interest relevant to this article were reported.

M.D., A.B., D.F., M.W., and M.C. performed the experiments, analyzed data, and wrote the article. A.J.J., K.F.H., S.K.G., S.M.H., and J.A.S. contributed to the design, conducted the study, and contributed to results and discussion. C.E.A. analyzed data and contributed to results and discussion. T.J.L. designed and conducted the study and wrote the article. T.J.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

The skilled and dedicated assistance with the clinical components of the study, provided by the following individuals, is acknowledged: Jill Mauldin and Mary Myers from the Medical University of South Carolina, Charleston; Jill Cole and Nancy Sprouse from the Spartanburg Regional Hospital, Spartanburg, South Carolina; Myrra Windau from the University of Colorado, Denver; Christine Knight, Jennifer Conn, Peter England, Susan Hiscock, Jeremy Oats, and Peter Wein from the University of Melbourne, Melbourne, Australia; Torun Clausen and Bjorg Lorentzen from the Oslo University Hospital, Oslo, Norway; and Azar Dashti, Lori Doyle, and Kenneth W. Wilson from the University of Oklahoma, Oklahoma City. The authors also acknowledge the scientific contributions of the following personnel: Alison J. Nankervis from The Royal Women’s Hospital, Australia; Hanne Scholz and Tore Henriksen from the University of Oslo; Kathryn M. Menard from the University of North Carolina; Paul Smith from the Oklahoma Medical Research Foundation; Yongxin Yu from the University of Oklahoma; and John R. Stanley from the Mercy Health Center, Oklahoma City, Oklahoma.

1.
Manten
GT
,
Sikkema
MJ
,
Voorbij
HA
,
Visser
GH
,
Bruinse
HW
,
Franx
A
.
Risk factors for cardiovascular disease in women with a history of pregnancy complicated by preeclampsia or intrauterine growth restriction
.
Hypertens Pregnancy
2007
;
26
:
39
50
[PubMed]
2.
Redman
CW
,
Sacks
GP
,
Sargent
IL
.
Preeclampsia: an excessive maternal inflammatory response to pregnancy
.
Am J Obstet Gynecol
1999
;
180
:
499
506
3.
de Jonge
LL
,
Steegers
EA
,
Ernst
GD
, et al
.
C-reactive protein levels, blood pressure and the risks of gestational hypertensive complications: the Generation R Study
.
J Hypertens
2011
;
29
:
2413
2421
[PubMed]
4.
Forest
JC
,
Charland
M
,
Massé
J
, et al
.
Candidate biochemical markers for screening of pre-eclampsia in early pregnancy
.
Clin Chem Lab Med
2012
;
50
:
973
984
[PubMed]
5.
Ertas
IE
,
Kahyaoglu
S
,
Yilmaz
B
, et al
.
Association of maternal serum high sensitive C-reactive protein level with body mass index and severity of pre-eclampsia at third trimester
.
J Obstet Gynaecol Res
2010
;
36
:
970
977
[PubMed]
6.
Molvarec
A
,
Szarka
A
,
Walentin
S
, et al
.
Serum leptin levels in relation to circulating cytokines, chemokines, adhesion molecules and angiogenic factors in normal pregnancy and preeclampsia
.
Reprod Biol Endocrinol
2011
;
9
:
124
[PubMed]
7.
Cemgil Arikan
D
,
Aral
M
,
Coskun
A
,
Ozer
A
.
Plasma IL-4, IL-8, IL-12, interferon-γ and CRP levels in pregnant women with preeclampsia, and their relation with severity of disease and fetal birth weight
.
J Matern Fetal Neonatal Med
2012
;
25
:
1569
1573
[PubMed]
8.
Montagnana
M
,
Lippi
G
,
Albiero
A
,
Salvagno
GL
,
Franchi
M
,
Guidi
GC
.
Serum pro-inflammatory cytokines in physiological and pre-eclamptic pregnancies
.
Gynecol Endocrinol
2008
;
24
:
113
116
[PubMed]
9.
Jonsson
Y
,
Rubèr
M
,
Matthiesen
L
, et al
.
Cytokine mapping of sera from women with preeclampsia and normal pregnancies
.
J Reprod Immunol
2006
;
70
:
83
91
[PubMed]
10.
Carty
DM
,
Anderson
LA
,
Freeman
DJ
, et al
.
Early pregnancy soluble E-selectin concentrations and risk of preeclampsia
.
J Hypertens
2012
;
30
:
954
959
[PubMed]
11.
Clausen
T
,
Djurovic
S
,
Brosstad
FR
,
Berg
K
,
Henriksen
T
.
Altered circulating levels of adhesion molecules at 18 weeks’ gestation among women with eventual preeclampsia: indicators of disturbed placentation in absence of evidence of endothelial dysfunction?
Am J Obstet Gynecol
2000
;
182
:
321
325
[PubMed]
12.
Kronborg
CS
,
Gjedsted
J
,
Vittinghus
E
,
Hansen
TK
,
Allen
J
,
Knudsen
UB
.
Longitudinal measurement of cytokines in pre-eclamptic and normotensive pregnancies
.
Acta Obstet Gynecol Scand
2011
;
90
:
791
796
[PubMed]
13.
Clausen
P
,
Ekbom
P
,
Damm
P
, et al
.
Signs of maternal vascular dysfunction precede preeclampsia in women with type 1 diabetes
.
J Diabetes Complications
2007
;
21
:
288
293
[PubMed]
14.
Yu
Y
,
Jenkins
AJ
,
Nankervis
AJ
, et al
.
Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women
.
Diabetologia
2009
;
52
:
160
168
15.
Azar
M
,
Basu
A
,
Jenkins
AJ
, et al
.
Serum carotenoids and fat-soluble vitamins in women with type 1 diabetes and preeclampsia: a longitudinal study
.
Diabetes Care
2011
;
34
:
1258
1264
[PubMed]
16.
Basu
A
,
Alaupovic
P
,
Wu
M
, et al
.
Plasma lipoproteins and preeclampsia in women with type 1 diabetes: a prospective study
.
J Clin Endocrinol Metab
2012
;
97
:
1752
1762
[PubMed]
17.
Jenkins
AJ
,
Rothen
M
,
Klein
RL
, et al
DCCT/EDIC Research Group
.
Cross-sectional associations of C-reactive protein with vascular risk factors and vascular complications in the DCCT/EDIC cohort
.
J Diabetes Complications
2008
;
22
:
153
163
[PubMed]
18.
Alex
P
,
Szodoray
P
,
Knowlton
N
, et al
.
Multiplex serum cytokine monitoring as a prognostic tool in rheumatoid arthritis
.
Clin Exp Rheumatol
2007
;
25
:
584
592
[PubMed]
19.
Ridker
PM
,
Cushman
M
,
Stampfer
MJ
,
Tracy
RP
,
Hennekens
CH
.
Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease
.
Circulation
1998
;
97
:
425
428
[PubMed]
20.
Emerging Risk Factors Collaboration
Kaptoge
S
,
Di Angelantonio
E
,
Pennells
L
, et al
.
C-reactive protein, fibrinogen, and cardiovascular disease prediction
.
N Engl J Med
2012
;
367
:
1310
1320
21.
Sesso
HD
,
Buring
JE
,
Rifai
N
,
Blake
GJ
,
Gaziano
JM
,
Ridker
PM
.
C-reactive protein and the risk of developing hypertension
.
JAMA
2003
;
290
:
2945
2951
[PubMed]
22.
Wolf
M
,
Kettyle
E
,
Sandler
L
,
Ecker
JL
,
Roberts
J
,
Thadhani
R
.
Obesity and preeclampsia: the potential role of inflammation
.
Obstet Gynecol
2001
;
98
:
757
762
[PubMed]
23.
Qiu
C
,
Luthy
DA
,
Zhang
C
,
Walsh
SW
,
Leisenring
WM
,
Williams
MA
.
A prospective study of maternal serum C-reactive protein concentrations and risk of preeclampsia
.
Am J Hypertens
2004
;
17
:
154
160
[PubMed]
24.
Loukovaara
S
,
Immonen
I
,
Koistinen
R
,
Hiilesmaa
V
,
Kaaja
R
.
Inflammatory markers and retinopathy in pregnancies complicated with type I diabetes
.
Eye (Lond)
2005
;
19
:
422
430
[PubMed]
25.
Li
H
,
Cybulsky
MI
,
Gimbrone
MA
 Jr
,
Libby
P
.
Inducible expression of vascular cell adhesion molecule-1 by vascular smooth muscle cells in vitro and within rabbit atheroma
.
Am J Pathol
1993
;
143
:
1551
1559
[PubMed]
26.
Price
DT
,
Loscalzo
J
.
Cellular adhesion molecules and atherogenesis
.
Am J Med
1999
;
107
:
85
97
27.
Clausen
P
,
Jacobsen
P
,
Rossing
K
,
Jensen
JS
,
Parving
HH
,
Feldt-Rasmussen
B
.
Plasma concentrations of VCAM-1 and ICAM-1 are elevated in patients with Type 1 diabetes mellitus with microalbuminuria and overt nephropathy
.
Diabet Med
2000
;
17
:
644
649
[PubMed]
28.
Schram
MT
,
Chaturvedi
N
,
Schalkwijk
C
, et al
EURODIAB Prospective Complications Study
.
Vascular risk factors and markers of endothelial function as determinants of inflammatory markers in type 1 diabetes: the EURODIAB Prospective Complications Study
.
Diabetes Care
2003
;
26
:
2165
2173
[PubMed]
29.
Gibson
JL
,
Lyall
F
,
Boswell
F
,
Young
A
,
Maccuish
AC
,
Greer
IA
.
Circulating cell adhesion molecule concentrations in diabetic women during pregnancy
.
Obstet Gynecol
1997
;
90
:
874
879
[PubMed]
30.
Ait-Oufella
H
,
Taleb
S
,
Mallat
Z
,
Tedgui
A
.
Recent advances on the role of cytokines in atherosclerosis
.
Arterioscler Thromb Vasc Biol
2011
;
31
:
969
979
[PubMed]
31.
Wegmann
TG
,
Lin
H
,
Guilbert
L
,
Mosmann
TR
.
Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?
Immunol Today
1993
;
14
:
353
356
[PubMed]
32.
Vince
GS
,
Starkey
PM
,
Austgulen
R
,
Kwiatkowski
D
,
Redman
CW
.
Interleukin-6, tumour necrosis factor and soluble tumour necrosis factor receptors in women with pre-eclampsia
.
Br J Obstet Gynaecol
1995
;
102
:
20
25
[PubMed]
33.
Pfleger
C
,
Mortensen
HB
,
Hansen
L
, et al
Hvidøre Study Group on Childhood Diabetes
.
Association of IL-1ra and adiponectin with C-peptide and remission in patients with type 1 diabetes
.
Diabetes
2008
;
57
:
929
937
[PubMed]
34.
Greer
IA
,
Lyall
F
,
Perera
T
,
Boswell
F
,
Macara
LM
.
Increased concentrations of cytokines interleukin-6 and interleukin-1 receptor antagonist in plasma of women with preeclampsia: a mechanism for endothelial dysfunction?
Obstet Gynecol
1994
;
84
:
937
940
[PubMed]
35.
Szarka
A
,
Rigó
J
 Jr
,
Lázár
L
,
Beko
G
,
Molvarec
A
.
Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array
.
BMC Immunol
2010
;
11
:
59
[PubMed]
36.
Shimada
A
,
Morimoto
J
,
Kodama
K
, et al
.
Elevated serum IP-10 levels observed in type 1 diabetes
.
Diabetes Care
2001
;
24
:
510
515
[PubMed]
37.
Ramsay
JE
,
Simms
RJ
,
Ferrell
WR
, et al
.
Enhancement of endothelial function by pregnancy: inadequate response in women with type 1 diabetes
.
Diabetes Care
2003
;
26
:
475
479
[PubMed]
38.
Thavasu
PW
,
Longhurst
S
,
Joel
SP
,
Slevin
ML
,
Balkwill
FR
.
Measuring cytokine levels in blood. Importance of anticoagulants, processing, and storage conditions
.
J Immunol Methods
1992
;
153
:
115
124
[PubMed]
39.
Kraus
TA
,
Sperling
RS
,
Engel
SM
, et al
.
Peripheral blood cytokine profiling during pregnancy and post-partum periods
.
Am J Reprod Immunol
2010
;
64
:
411
426
[PubMed]
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