Coagulation inhibitors in preeclamptic pregnant women

Objective Our objective was to detect clinical evaluation of coagulation inhibitors in preeclamptic and normotensive pregnant women and to determine their important role in pathogenesis of preeclampsia.Methods A total of 20 mild, 20 severe preeclamptic and 45 normotensive pregnant women were included in this study. The plasma value of antithrombin III (AT-III) activity, proteins C and S activity, PT, PTT, fibrinogen and platelet counts were determined.Results The values AT-III were lower in women with severe preeclampsia than in controls (p<0.05). In all groups, there was no significantly difference in the concentration of protein C activity, protein S and fibrinogen (p>0.05). The plasma thrombocyte counts were significantly lower in severe preeclamptic women than in normotensive women (p<0.05). There was no significant difference in the prothrombin time value in all groups, but a significantly difference with regard to partial thromboplastin time between severe preeclamptic and the control group (p<0.0001). It was longer than the control.Conclusion The markers of hemostasis activation such as protein S, protein C activity together with fibrinogen levels are not useful tools but the reduction of AT-III and platelet counts would seem useful in different pathological situations in pregnancy to predict and monitor the severity of the condition.     

Evaluation of B-type natriuretic peptide (BNP) levels in normal and preeclamptic women

OBJECTIVE: B-type natriuretic peptide (BNP) is synthesized in cardiac ventricles in response to volume expansion. This study evaluated BNP levels to determine trends during pregnancy, and to assess BNP as a diagnostic tool in preeclampsia. STUDY DESIGN: We studied 163 BNP levels in 118 pregnant women, ranging from first trimester to term. An additional 34 patients with preeclampsia were studied and compared to 25 normal control patients at term. Plasma BNP values were determined using a standard assay. RESULTS: The median BNP levels during the 1st, 2nd, 3rd trimester, and at term were equivalent (18.4, 17.9, 15.5, and 17.8 pg/mL, respectively, P = .796). The median BNP levels in normal patients, mild preeclamptics, and severe preeclamptics were 17.8, 21.1, and 101 pg/mL, respectively, with the severe group being significantly higher than the mild group (P = .003) and any phase of normal pregnancy (P < .001 in each case). A BNP cut-off of <40.6 pg/mL had a negative predictive value of 92% in excluding preeclampsia. CONCLUSION: In normal pregnancies, median BNP values are <20 pg/mL, and stable throughout gestation. In severe preeclampsia BNP levels are elevated. This may reflect ventricular stress and/or subclinical cardiac dysfunction associated with preeclampsia.     

Association between allelic variants in cytokine genes and preeclampsia

OBJECTIVE: The purpose of this study was to examine the relationship between cytokine genotypes and preeclampsia. STUDY DESIGN: We conducted a case-control study that examined cytokine genotypes among 150 primiparous preeclamptic women and 661 primiparous, normotensive women. Analyses were adjusted for age, prepregnancy cigarette smoking, and education. RESULTS: Preeclamptic white women were more likely than normotensive white women to carry the up-regulating tumor necrosis factor-alpha-308 A/A (odds ratio, 4.1; 95% CI, 1.1-15.3) genotype. Both black and white women with preeclampsia were more likely than normotensive control subjects to carry the interleukin-1alpha-producing-4845 G/G genotype (black odds ratio, 11.6; 95% CI, 1.5-89.3; white odds ratio, 1.7; 95% CI, 0.7-3.9), -889 C/C genotype (black odds ratio, 5.1; 95% CI, 0.6-41.6; white odds ratio, 1.9; 95% CI, 0.8-4.7), and the interleukin-1alpha-4845/interleukin-1alpha-889/interleukin-1beta-3957 GCC/GCC haplotype (black odds ratio, 3.4; 95% CI, 1.3-8.7; white odds ratio, 2.1; 95% CI, 1.4-3.2). CONCLUSION: Cytokine genotypes were associated with preeclampsia and may identify women who are at high risk for preeclampsia.     

Serum calcium and serum magnesium in normal and preeclamptic pregnancy

Objective The aims of this study were to measure serum levels of calcium and magnesium in preeclamptic pregnancies and to compare them with those in normal pregnancies.Materials and methods We collected venous serum samples from 40 preeclamptic pregnant women and 40 normal pregnant women. The blood samples were analyzed for calcium and magnesium, using a colorimetric analyzer. The data were analyzed using the Student’s t-test, χ ²-test or Fisher exact tests when appropriate.Results The serum calcium concentration in preeclamptic pregnant women is significantly lower than that in normal pregnant women (9.0±0.4 mg/dl vs. 9.7±0.7 mg/dl, p<0.0001). Like serum calcium, serum magnesium concentration in preeclamptic women is significantly lower than that in normal pregnant women (0.77±0.08 mmol/l vs. 0.85±0.09 mmol/l, p=0.001).Conclusion This study shows that both serum calcium and serum magnesium levels in preeclamptic pregnant women are lower than in normal pregnant women. These findings support the hypothesis that hypocalcemia and hypomagnesemia are possible etiologies of preeclampsia.     

Elevated soluble Fas ligand levels may suggest a role for apoptosis in women with endometriosis

OBJECTIVE: To evaluate soluble Fas ligand concentrations in serum and peritoneal fluid from women with endometriosis and from fertile controls without endometriosis, and to study levels of soluble Fas ligand in conditioned media of cultured endometrial stromal cells. DESIGN: Prospective, experimental trial. SETTING: Two academic IVF centers. PATIENT(S): Twenty-nine fertile women without endometriosis and 57 infertile women with endometriosis (32 with stage I or II disease and 25 with stage III or IV disease). MAIN OUTCOME MEASURE(S): Enzyme-linked immunosorbent assay was used to measure soluble Fas ligand concentrations in paired samples of serum and peritoneal fluid from women with and without endometriosis. Concentrations were also measured in conditioned media of cultured endometrial stromal cells at basal conditions and after stimulation with interleukin-8 (0.001-10 ng/mL) and tumor necrosis factor-alpha (1-10 ng/mL). RESULT(S): Compared with fertile controls and women with early-stage of endometriosis, women with moderate to severe endometriosis had elevated serum (87.2 +/- 6.4, 88.2 +/- 6.9, and 162.3 +/- 7.8 pg/mL, respectively) and peritoneal fluid (81.0 +/- 6.0, 80.5 +/- 6.8, and 166.2 +/- 10.3 pg/mL, respectively) concentrations of soluble Fas ligand. Serum levels of soluble Fas ligand positively correlated with levels in peritoneal fluid. Comparison of patients in the same menstrual cycle in each group revealed that increased levels of soluble Fas ligand in patients with advanced endometriosis were not attributable to the difference in cycle phases. Soluble Fas ligand was not detected in conditioned media of endometrial stromal cells under baseline conditions or after stimulation. CONCLUSION(S): Serum and peritoneal fluid of women with moderate to severe endometriosis contain elevated concentrations of soluble Fas ligand compared to women with minimal or mild endometriosis and women without endometriosis. These findings suggest a role for apoptotic dysregulation in the pathophysiology of endometriosis.     

Endothelial nitric oxide synthase (eNOS) gene Glu298Asp polymorphism and expression in North Indian preeclamptic women

BackgroundPathophysiological processes in preeclampsia (PE) are influenced by genetic factors, nitric oxide synthases seem to play important roles, although their expression in and their role is still unclear. To better characterize the host genetic factors determining the susceptibility to PE, we evaluated the influence of polymorphisms (Glu298Asp) in the endothelial nitric oxide synthase (eNOS) gene on the risk of developing PE by checking the expression level.MethodsWe conducted a hospital-based case-control study including 300 women with preeclampsia and 200 healthy pregnant women. Their blood samples were analyzed for levels of nitric oxide, eNOS gene polymorphism and expression. eNOS mRNA levels were determined using RT-PCR and expressed as arbitrary units after correction with control β-Actin gene mRNA levels.ResultsThe mRNA expression of eNOS gene was found to be significantly lower in blood (P < 0.05) from women with PE compared to that from normal pregnancies. The total nitric oxide levels (P < 0.001) were decreased in study Group as compared to healthy pregnant patients. The intergenotypic variation of nitric oxide levels in preeclamptic women was found to be significant (P < 0.001).ConclusionsThese results indicate the relationship between reduced nitric oxide levels and eNOS gene polymorphism leading to its altered expression in preeclamptic women.     

Serum concentrations of soluble Fas antigen and soluble Fas ligand in mother and newborn

We measured soluble Fas antigen and soluble Fas ligand, which are considered to be an apoptotic substance, in maternal serum, umbilical cord serum and amniotic fluid during cesarean section at full term pregnancy. Seventeen healthy parturients with no fetal distress were studied. Soluble Fas antigen showed no different levels between these measurement sites. Soluble Fas ligand showed a difference, in which umbilical serum level was significantly higher than maternal serum and amniotic fluid levels. The present results suggest high serum levels of soluble Fas ligand in newborn. However, the reason for this evidence is entirely unknown. Received: April 1999 / Accepted: 29 June 1999     

Elevated inflammatory markers in preeclamptic pregnancies,but no relation to systemic arterial stiffness

ObjectivesTo investigate if circulating markers of systemic and vascular inflammation are associated with systemic arterial properties at term and 6 months post-partum in women with preeclampsia (PE) and normal pregnancy (NP).Study designLongitudinal, sampling at term and 6 months post-partum in 34 women (32 ± 6 years) with PE and 61 women (32 ± 5 years) with NP.Main outcome measuresCirculating markers related to systemic and vascular inflammation were measured by enzyme immune-assay. Systemic arterial properties were estimated by Doppler (transthoracic echocardiography) and calibrated right subclavian artery pulse traces.ResultsCXCL16, soluble tumor necrosis factor receptor type 1 (sTNF-R1), monocyte chemoattractant peptide 1, pentraxin 3 and soluble vascular adhesion molecule 1 (sVCAM-1) were elevated at term in PE, and sTNF-R1 remained elevated 6 months post partum compared to NP. However, apart from a negative correlation between mean arterial pressure and sTNF-R1 and sVCAM-1 at term, no associations between systemic and vascular inflammatory markers and systemic arterial properties as reflected by characteristic impedance and arterial elastance, representing proximal aortic stiffness and effective arterial elastance, were found at any time point.ConclusionsPreeclamptic pregnancies are characterized by increased circulating levels of systemic and vascular inflammatory markers. However, these are not associated with systemic arterial properties at term or 6 months post partum.     

Fas and FasL genetic polymorphisms in women with recurrent pregnancy loss: a case-control study

Aberrant apoptosis at the trophoblast–maternal interface and abnormal expression of Fas and Fas ligand (FasL) have been reported in complicated pregnancies with recurrent pregnancy losses (RPL) and preeclampsia. We assessed the prevalence of Fas and FasL genetic polymorphisms in Korean women with RPL and in fertile controls. In total, 306 women with RPL and 298 fertile controls were enrolled. Genotype distributions of Fas and FasL in RPL patients versus fertile controls were examined under the Hardy–Weinberg equilibrium. Fas ?670 A/G genotype (AA versus AG versus GG, p?=?0.340) and allele frequencies (A versus G, p?=?0.412) were not different between the RPL and control groups. There was no difference in each Fas ?1377?G/A and FasL ?844 C/T genotype, and their allele frequencies. In addition, the unions of two zygosities of each genotype and their combined genotypes did not differ between two groups. No difference in the prevalence of Fas and FasL single-nucleotide polymorphisms (SNPs) was observed between women with RPL and fertile controls among Korean women. To determine the possibility of genetic polymorphisms in Fas and its ligand as risk factors for RPL, further studies in various races and a large study population are needed.     

Maternal levels of vitamin E in normal and preeclamptic pregnancy

Vitamin E, a potent antioxidant, may play a role in preventing preeclampsia. Maternal blood samples were collected between 28 and 40 weeks’ gestation from women with mild preeclampsia (n=17), women with severe preeclampsia (n=16) and the control group (n=15). This control group was consisted of 15 pregnant women without hypertension episode during their pregnancy. Vitamin E levels were significantly higher in normotensive pregnant women (1.00±0.20 mg/dL) than in those with mild (0.56±0.15 mg/dL) or severe (0.37±0.75 mg/dL) preeclampsia (P<0.001). In preeclamptic women, when systolic blood pressure increases, maternal levels of vitamin E significantly decrease (P<0.05), also when diastolic blood pressure increases, maternal levels of vitamin E significantly decrease (P<0.05). Measurement of vitamin E concentration in plasma may be useful as a prognostic marker of the likely development of preeclampsia. Received: May 1999 / Accepted: 7 December 1999     

Polymorphisms in the inflammatory pathway genes and the risk of preeclampsia in Sinhalese women

Objective: Elevated pro-inflammatory cytokines play an important role in the pathogenesis of preeclampsia. We investigated the prevalence of functional polymorphisms in genes regulating inflammation in preeclamptic women.

Methods: One hundred seventy-five nulliparous Sinhalese women with preeclampsia (cases) and 171 normotensive women matched for age, ethnicity, parity and body mass index (BMI) (controls) were recruited. Preeclampsia was diagnosed using international guidelines. Genotyping was performed on DNA extracted from peripheral blood using the Sequenom MassARRAY system.

Results: The prevalence of the CT genotype of IL1A rs17561 polymorphism was increased in preeclamptic women compared with controls {p?=?0.04, odds ratio (OR) [95% class interval (CI)]?=?1.6 (1.0–2.5)}. The prevalence of the CT genotype [p?=?0.01, OR (95% CI)?=?1.8 (1.1–2.8)] and the dominant model (CT?+?TT) [p?=?0.03, OR (95% CI)?=?1.6 (1.1–2.5)] of the IL1A rs1800587 polymorphism were increased in preeclamptic women compared with controls. The prevalence of the GA genotype [p?=?0.04, OR (95% CI)?=?0.6 (0.4–0.9)] and the dominant model (GA?+?AA) [p?=?0.03, OR (95% CI)?=?0.6 (0.4–0.9)] of the MBL1 rs1800450 polymorphism were reduced in preeclamptic women compared to controls.

Conclusion: Genotypes conferring a pro-inflammatory phenotype are increased in preeclamptic women.     

Inflammatory Mediators Gene Polymorphisms in Preeclampsia

Objective. To assess a possible relation between proinflammatory mediators (IL-1R1, IL-12, IL-18, TLR-2, and TLR-4) gene polymorphisms and preeclampsia (PE). Methods. Genotyping was performed on 109 preeclamptic patients and 174 healthy fertile women with at least two previous successful pregnancies (controls). χ² or Fisher's exact test were used to compare genotype frequencies. The control group included 174 pregnant women matched by race to the study group. Results. Genotypic and allelic distributions for all six polymorphisms were similar between the study and control groups. IL-1R1 (PstI, rs2234650): p = 0.82 ; IL-12 (+1188, rs3212227): p = 0.93; IL-18 (?137, rs187238): p = 0.74 ; IL-18 (?607, rs1946519): p = 0.22; TLR-2 (+2258, rs5743708): p = 0.97; and TLR-4 (+896, rs4986790): p = 0.23. Conclusion. The analyzed gene polymorphisms are not associated with PE.     

L-Arginine erythrocyte transport in normal pregnant and preeclamptic women

OBJECTIVE: Uptake of L-arginine by the cell via amino acid transporter systems is the first step for nitric oxide (NO) production. The current study aimed to assess the total L-arginine uptake in erythrocytes of normal pregnant and preeclamptic women. STUDY DESIGN: Twenty-one normal pregnant and 21 preeclamptic women were studied. To measure total L-arginine uptake in erythrocytes, carbon 14 was used as a marker and Michaelis-Menten kinetic parameters (V(max) and K(m)) were evaluated. RESULTS: In preeclamptic women, there was a significant increase (P<.004) in the mean maximal capacity of transport in erythrocytes (V(max)=982.69 micromol/L cells/h+/-433.51) in comparison with normal pregnant women (V(max)=584.73 micromol/L cells/h+/-422.33). No significant difference was detected in the half-saturation constant (P=0.978). CONCLUSION: The transport kinetics of the NO precursor, L-arginine, is altered in erythrocytes of preeclamptic women. It is possible that abnormal L-arginine uptake may contribute to the pathophysiologic mechanisms of preeclampsia syndrome.     

Vasorelaxant effect of levcromakalim on isolated umbilical arteries of preeclamptic women

OBJECTIVE: Potassium channel openers are revealed to be a new type of antihypertensive drug. We aimed to clarify the effects of levcromakalim, an ATP-sensitive potassium channel opener, on human isolated umbilical artery (UA) and to compare them with those of nifedipine and magnesium sulphate, which are currently used in the treatment of preeclampsia (PE). STUDY DESIGN: A total of 52 umbilical arteries, isolated immediately after delivery from 27 healthy and 25 preeclamptic pregnant women, were placed into 10-ml organ baths filled with Kreb's solution at physiological pH and temperature. The concentration-dependent relaxations in response to levcromakalim, nifedipine and magnesium sulphate were compared in vessels precontracted with serotonin (1 micromol/l). RESULTS: The maximal relative relaxation responses (E(max), expressed as percentage of serotonin-induced precontraction) to magnesium sulphate, nifedipine and levcromakalim in umbilical arteries were identical in the healthy (85.06+/-3.31, 84.80+/-3.01 and 80.37+/-5.32%, respectively) and preeclamptic (77.20+/-5.30, 83.36+/-2.37 and 79.13+/-4.30%, respectively) groups. CONCLUSION: Levcromakalim has a vasodilatory effect on the umbilical artery like magnesium sulphate and nifedipine, and serves as an antihypertensive potential that might be used in the treatment of preeclampsia. However, further experimental and clinical studies are needed to propose that ATP-sensitive potassium channel openers are beneficial drugs in cases of clinical preeclampsia.     

Side-to-side differences in transcranial Doppler parameters in normotensive and preeclamptic pregnant women

OBJECTIVE: This study was undertaken to investigate whether women with preeclampsia demonstrate larger side-to-side velocity differences in the middle cerebral artery (MCA) compared with normotensive pregnant women. STUDY DESIGN: Forty-one preeclamptic women and 50 normotensive pregnant women were studied during the third trimester. Transcranial Doppler ultrasound was used to measure peak, end-diastolic, and mean velocities in both MCAs. An asymmetry index was calculated as 100 x Rt-Lt//(Rt+Lt)/2, for each of the following parameters: mean velocity (Vm), pulsatility index (PI), and cerebral perfusion pressure (CPP). Student t test, Pearson correlation, and regression analysis were used. Significance was taken as P<.05. RESULTS: Both normotensive and preeclamptic pregnant women showed good correlation between Rt and Lt MCA Vm (R>0.8, P<.0001), PI (R>0.6, P.0001), and CPP (R>0.8, P<.0001). There were no differences in the asymmetry index for Vm, PI, or CPP between the two groups. CONCLUSION: Preeclampsia does not appear to induce greater side-to-side velocity differences in the MCA distribution.     

Neurokinin B peptide serum levels are higher in normotensive pregnant women than in preeclamptic pregnant women

OBJECTIVES: The purpose of this study was to examine neurokinin B levels in serum from preeclamptic and normotensive and to investigate the role of neurokinin B in preeclampsia. STUDY DESIGN: Peripheral and uterine venous blood neurokinin B levels were measured in 14 normotensive and 8 preeclamptic pregnant women by radioimmunoassay. RESULTS: Neurokinin B levels in normotensive women were 4.91 +/- 2.67 nmol/L in peripheral and 5.59 +/- 2.06 nmol/L in uterine blood. In pregnant women with preeclampsia, neurokinin B levels were 2.79 +/- 1.68 nmol/L and 3.20 +/- 1.55 nmol/L, respectively. Neurokinin B levels were significantly higher in normotensive women (P=.032 in peripheral and P=.006 in uterine blood). CONCLUSIONS: Neurokinin B serum levels were higher in normotensive women. Higher neurokinin B concentrations in normotensive pregnant women may be due to the advanced gestational age and/or the result of a negative interaction of other vasoactive substances. The role of neurokinin B in preeclampsia remains to be determined.     

Contribution of TIMP3 polymorphisms to the development of preeclampsia in Han Chinese women

Purpose

The aim of this study was to investigate whether polymorphisms in the tissue inhibitor of metalloproteinase 3 gene (TIMP3) are associated with the risk of preeclampsia (PE) in Han Chinese women.

Methods

Nine single TIMP3 tag-single nucleotide polymorphisms were selected by Haploview and genotyped using the Sequenom method in 181 preeclamptic and 203 healthy pregnant women from eastern China.

Results

The allele frequencies of the tag-single nucleotide polymorphisms were not significantly different between groups (P > 0.05). However, the genotype distribution of rs135025 was shown to differ between the multigravidity PE subgroup (>3) and controls under additive (P = 0.018) and recessive models (P = 0.008), while the genotype distribution of rs80272 differed significantly between the severe PE subgroup and controls under additive (P = 0.014) and dominant models (P = 0.041). Moreover, the H2 haplotype (A-C-G-T-A-A-G-C-G) was found to be associated with the risk of PE (P = 0.035).

Conclusions

Genotypes of rs135025 and rs80272 in TIMP3 may therefore influence susceptibility to PE, and pregnant women carrying the H2 haplotype might be more prone to developing PE.

Electronic supplementary material

The online version of this article (doi:10.1007/s10815-015-0529-8) contains supplementary material, which is available to authorized users.