Is there evidence of separate inflammatory or metabolic forms of preeclampsia?

OBJECTIVES: To examine whether high insulin resistance versus high inflammation identifies subtypes of preeclampsia. METHODS: A cytokine panel, glucose and insulin were measured in 37 preeclampsia plasma samples. Wilcoxon rank sum assessed median concentration of HOMA(IR) by pro-inflammatory:anti-inflammatory ratio. Regression stratifying by BMI and preterm birth was conducted. RESULTS: There was no difference in median HOMA(IR) by the pro-inflammatory:anti-inflammatory ratio (p = 0.16). No subsets scatterplot clusters emerged. A positive correlation between HOMAlog and the ratio was significant (p = 0.04). CONCLUSIONS: No dichotomous subsets of preeclampsia by inflammation versus insulin resistance were detected. Contrary to our hypothesis, insulin resistance was higher as inflammation increased in preeclampsia.

Cigarette smoking during pregnancy: chromosome translocations and phenotypic susceptibility in mothers and newborns.

The effects of maternal cigarette smoking during pregnancy on structural chromosome aberrations were evaluated in peripheral lymphocytes from 239 mothers and their 241 newborns to determine whether smoking during pregnancy, genetic susceptibility, and race are associated with chromosome aberrations including translocations. Demographic information and cigarette smoking data were obtained via questionnaire. There were 119 Caucasian Americans, 118 African Americans, and 2 Asian Americans. The average maternal age was 24.9+/-5.8 (mean+/-S.D.) years. Thirty-nine percent of the Caucasian Americans and 45.4% of the African Americans self-reported that they were active smokers during the index pregnancy. The average number of cigarettes smoked per day was 2.65+/-5.75 and 1.37+/-3.17 for Caucasian and African American mothers, respectively. Peripheral blood lymphocytes from the mother and from the fetal side of the placenta were evaluated for chromosome aberrations by whole chromosome painting. Aliquots from the same blood samples were also used to assess genetic susceptibility with an in vitro bleomycin challenge assay. Spontaneous translocation frequencies in both maternal and newborn lymphocytes were not associated with cigarette smoking, socioeconomic status, or education. The absence of a smoking effect may be attributable to the low level of cigarette usage in these subjects. The average bleomycin-induced damage in the maternal and newborn populations was 0.37+/-0.27 and 0.15+/-0.14 breaks per cell, respectively, a difference that was highly significant (p<0.0001). In newborns there was a positive association between bleomycin sensitivity and the frequencies of aberrations as measured by chromosome painting: p

Increased myeloperoxidase in the placenta and circulation of women with preeclampsia.

Myeloperoxidase (MPO) is a hemoprotein normally released from activated monocytes and neutrophils. Traditionally viewed as a microbicidal enzyme, MPO also induces low-density lipoprotein oxidation, activates metalloproteinases, and oxidatively consumes endothelium-derived NO. The elevated plasma MPO level is a risk factor for myocardial events in patients with coronary artery disease. Patients with preeclampsia display evidence of the inflammation and endothelial dysfunction associated with oxidative stress in the circulation, vasculature, and placenta. We hypothesized that MPO levels in the circulation and placental extracts from women with preeclampsia would be greater than levels in women with normal pregnancies. Placental extracts were prepared from placental villous biopsies from preeclamptic (n=27) and control (n=43) placentas. EDTA plasma samples were obtained from gestationally age-matched preeclamptic and control normal pregnancies. MPO concentrations were measured by ELISA. Immunohistochemistry was used to determine MPO localization in the placenta. MPO levels in placental extracts from women with preeclampsia were significantly higher than the levels in normal control subjects (546+/-62 versus 347+/-32 ng/mL; P=0.025). MPO was found in the floating villi and basal plate of placentas with a greater staining in the basal plates from preeclampsia placentas compared with normal pregnancies. Plasma MPO levels were 3-fold higher in patients with preeclampsia compared with normal control subjects (36.6+/-7.6 versus 11.0+/-3.1 ng/mL; P=0.003). In conclusion, MPO levels are significantly increased in the circulation and placenta of women with preeclampsia. We speculate that MPO may contribute to the oxidative damage reported in the endothelium and placenta of women with preeclampsia.

Cigarette smoke exposure and angiogenic factors in pregnancy and preeclampsia.

BACKGROUND: Cigarette smoking during pregnancy is paradoxically associated with a reduced risk of developing preeclampsia. Both smoking and preeclampsia are associated with alterations in circulating angiogenic factors. The objective of this study was to investigate the relationship between cigarette smoking and the angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in pregnant women with and without preeclampsia. METHODS: Plasma sFlt-1, PlGF, and cotinine were measured using enzyme-linked immunosorbent assay in 125 women with uncomplicated pregnancies (controls) and 58 women with preeclampsia. RESULTS: In uncomplicated pregnancies, maternal sFlt-1 concentrations were lower in smokers compared to nonsmokers (779.6 (487.5-1,140.8) vs. 1,116.5 (793.6-1,905.2) pg/ml, P < 0.005). Preeclamptic women who smoked also demonstrated a trend toward lower concentrations of sFlt-1 compared to nonsmokers (3,423.0 (2,183.4-5,689.0) vs. 5,504.9 (3,418.0-6,361.3) pg/ml, P = 0.07). Maternal PlGF concentrations were higher in smokers with uncomplicated pregnancies (398.4 (165.2-621.7) vs. 191.4 (104.6-446.8) pg/ml); however, this was not a statistically significant difference (P = 0.07). PlGF concentrations were not different in preeclamptic smokers compared to nonsmokers. The sFlt/PlGF ratio was significantly lower in smokers with uncomplicated pregnancies, but not in smokers with preeclampsia compared to nonsmokers. CONCLUSIONS: Cigarette smoking is associated with lower maternal sFlt-1 concentrations during pregnancy and preeclampsia. On the basis of these data, cigarette smoke exposure may decrease the risk of preeclampsia in part by moderating the anti-angiogenic phenotype observed in the syndrome.

Postpartum adiponectin concentration, insulin resistance and metabolic abnormalities among women with pregnancy-induced disturbances.

The authors compared postpartum adiponectin levels among women with prior pregnancy-induced disturbances and assessed their association with homeostasis model assessment for insulin resistance (HOMA-IR), the metabolic syndrome (MS), and the Framingham risk score (FRS). Women delivering in 1998 through 2001 and who had gestational diabetes mellitus (n=22), gestational hypertension (n=32), or preeclampsia (n=34) were examined 1 to 2 years after delivery and were grouped-matched to controls (n=29) by age and prepregnancy body mass index. HOMA-IR was increased, adiponectin values were decreased, and there was a higher MS prevalence in women with prior gestational diabetes mellitus (all P<.05). Adiponectin levels were inversely related to HOMA-IR (r=-0.45; P<.0001) and FRS (r=-0.25; P=.007), and a significant trend for decreasing adiponectin values with increased number of MS components was noted (P trend <.0001). Adiponectin concentration remained a significant correlate of FRS and MS irrespective of pregnancy history; a concentration <10.5 microg/mL provided the optimal cutoff to distinguish those with or without MS. Thus, a lower postpartum adiponectin concentration identifies women at increased cardiovascular risk regardless of pregnancy history.

A comparison of circulating TNF-alpha in obese and lean women with and without preeclampsia.

OBJECTIVES: We hypothesized that TNF-alpha would be higher in obese versus lean women with preeclampsia. METHODS: Total plasma TNF-alpha was measured in a nested case-control study of 123 nulliparous lean and obese control women and women with preeclampsia. RESULTS: Adjusted mean TNF-alpha concentrations were 0.97 +/- 0.11 (pg/mL +/- SEM) in lean controls, 1.01 +/- 0.10 in obese controls, 1.43 +/- 0.11 in lean women with preeclampsia and 1.16 +/- 0.11 in obese women with preeclampsia. Pregnancy outcome was the single predictor of TNF-alpha concentration in the general linear regression model (p = 0.04). CONCLUSION: TNF-alpha concentration was higher in preeclampsia compared with control subjects. Obesity was not associated with higher TNF-alpha concentrations in either preeclampsia or control subjects.

Inflammation and triglycerides partially mediate the effect of prepregnancy body mass index on the risk of preeclampsia.

The objective of this study was to quantify the mediating role of inflammation and triglycerides in the association between prepregnancy body mass index (weight (kg)/height (m)2) and preeclampsia. The authors conducted a nested case-control study of 55 preeclamptic women and 165 pregnant controls from the Pregnancy Exposures and Preeclampsia Prevention Study (Pittsburgh, Pennsylvania, 1997-2001). Serum samples collected at < or = 20 weeks' gestation were analyzed for levels of C-reactive protein and triglycerides. The adjusted odds ratio (AOR) from a multivariable conditional logistic regression model assessing the total effect of body mass index on preeclampsia risk was compared with the AOR from the same model after results were controlled for C-reactive protein, triglycerides, and confounding factors (direct-effects model). The percentage of the total effect that was mediated through inflammation and triglycerides was calculated as 100 - [ln(direct-effects AOR)/ln(total-effects AOR)]. In the total-effects model, 4- and 8-unit increases in body mass index were associated with 1.7-fold (95% confidence interval (CI): 1.3, 2.3) and 2.9-fold (95% CI: 1.6, 5.2) increases in preeclampsia risk, whereas in the direct-effects model, these AORs were 1.4 (95% CI: 1.0, 1.9) and 2.0 (95% CI: 1.0, 3.8), respectively. Inflammation was a more important mediator than triglycerides. These findings suggest that approximately one third of the total effect of body mass index on preeclampsia risk is mediated through inflammation and triglyceride levels.

Maternal plasma homocysteine concentrations are not increased in twin pregnancies.

OBJECTIVE(S): We tested the hypothesis that twin pregnancies would lead to increased maternal plasma homocysteine. We further hypothesized that twin pregnancies complicated by preeclampsia would have increased plasma homocysteine compared to twin pregnancies without preeclampsia and normal singleton pregnancies. METHODS: Plasma was collected at delivery from 127 nulliparous subjects: 57 women with normal singleton pregnancies, 39 women with singleton and preeclampsia, 17 women with uncomplicated twin pregnancies, and 14 women with twins and preeclampsia. Subjects were group matched for prepregnancy body mass index (BMI) and race. Plasma homocysteine was analyzed by high pressure liquid chromatography (HPLC) with fluorescence detection, and plasma folic acid was measured by radio immunoassay (RIA). RESULTS: The mean plasma concentration of homocysteine was significantly increased in all women with preeclampsia (7.4+/-2.9 microM) compared to all normal pregnant women (5.9+/-2.1 microM, p=0.002). However, homocysteine was not significantly increased in all women with twins (6.7+/-2.1 microM) compared to all women with singleton pregnancies (6.5+/-2.7 microM, p=0.61). In addition, women with twins and preeclampsia did not have increased homocysteine (6.8+/-2.1 microM) compared to women with twins and normal pregnancy (6.7+/-2.1 microM, p=0.72). As expected, because of extra supplementation, plasma folic acid was significantly increased in women with twins (27.9+/-11.6 ng/mL) compared to women with singleton pregnancies (20.8+/-8.5 ng/mL, p=0.0003). However, folic acid was not different between preeclamptics and controls (23.5+/-10.8 vs. 21.9+/-9.2 ng/mL respectively, p=0.36). Lastly, there was a significant inverse correlation between homocysteine and folic acid among all the subjects (r2=- 0.053, p< 0.01), and this correlation persisted in the women with singleton pregnancies (r2=- 0.078, p< 0.01), but was lost in the twins (r2=- 0.073, p=0.14). CONCLUSIONS: With contemporary management including increased folic acid supplementation, plasma homocysteine is not increased in twin pregnancies with or without preeclampsia.