Vascular endothelial growth factor and its receptors regulation in gestational diabetes mellitus and eclampsia.

BACKGROUND: An imbalance in the expression of vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) during pregnancy plays an important role in the pathogenesis of gestational diabetes mellitus (GDM) and eclampsia. VEGF and its receptors change during the regulation of blood vessels as a result of risk factors such as familial genetics. These modifications include loss of original balance of serological indicators, upregulation or downregulation of growth factor indicators, and changes in the placenta, kidney, liver and other organs to varying degrees of damage. This has an impact on both the pregnant woman's and the fetus's health. MAIN BODY: This paper summarizes the mechanisms of unbalanced VEGF and receptor expression based on data from relevant literature on GDM and eclampsia. An Imbalance in VEGF and its binding receptor is often associated with the occurrence of multiple pregnancy disorders. In recent years, researchers have focused on the potential role of VEGF and its receptors in the development of GDM and eclampsia. CONCLUSION: This paper summarizes the different VEGF subtypes and their binding receptors, as well as mechanisms that cause GDM and eclampsia, in order to provide valuable data to inform monitoring, diagnosis, and prognosis.

[Iron metabolism in women with anemia and eclampsia (Part I)].

The review deals with a modern view of iron exchange in general and during pregnancy, in particular Different views on the mechanisms of the development of anemia in pregnancy are reflected. The protective role of anemia is noted, and also the opinion of the review authors to the negative role of prophylactic supplementation of iron is reflected. Are numerous and compelling scientific evidence pointing to the large number of negative prevention of iron. That questioned the usefulness of routine appointments for pregnant women with iron. According to a large number of studies assigning pregnant iron on the one hand, contributes to excessive activation of free radical oxidation, the accumulation of lipid peroxidation products and demonstrations of eclampsia, and from the other potentiates the bacterial aggression and development of purulent-septic diseases that generally leads to the development of complications in pregnancy.

[Role of uric acid in preeclampsia-eclampsia]. / Papel del ácido úrico en la preeclampsia-eclampsia.

Uric acid is a terminal metabolite of the degradation of nucleotides, which increases their blood levels in patients with preeclampsia-eclampsia, increasing its synthesis by damage and death of trophoblastic cells in proliferation and decreased urinary excretion due a lower glomerular filtration rate and increased absorption in the proximal tubule. Hyperuricemia (> 4.5 mg/dL) is the first biomarker of the clinical chemistry considered as an early evidence of disease (< or = 20 weeks gestation). Uric acid concentrations are not only a criterion for establishing the correct diagnosis and the differential with other hypertensive states, but an indication of termination of pregnancy, often by cesarean section. Hyperuricemia has also demonstrated its usefulness as a predictor of maternal and fetal complications and maternal sequelae of late postpartum. Several studies have demonstrated its influence on the genesis of preeclampsia-eclampsia, either alone or jointly with other known processes (metabolic syndrome, oxidative stress, inflammation cascade, angiogenesis) that have a proven role in perpetuating the endothelial damage and maternal vascular smooth muscle cells. Further research is needed in large-scale clinical and experimental studies that expand our knowledge about the usefulness of uric acid as a biomarker of preeclampsia-eclampsia to allow early prevention and reducing the prevalence.

Acid Sensing Ion Channel 2a Is Reduced in the Reduced Uterine Perfusion Pressure Mouse Model and Increases Seizure Susceptibility in Pregnant Mice.

Eclampsia is diagnosed in pregnant women who develop novel seizures. Our laboratory showed that the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia displays reduced latency to drug-induced seizures. While acid sensing ion channels (ASIC1a and 3) are important for reducing seizure longevity and severity, the role of ASIC2a in mediating seizure sensitivity in pregnancy has not been investigated. We hypothesized that 1) RUPP reduces hippocampal ASIC2a, and 2) pregnant mice with reduced ASIC2a (ASIC2a+/-) have increased seizure sensitivity. On gestational day 18.5, hippocampi from sham and RUPP C57BL/6 mice were harvested, and ASIC2a was assessed using Western blot. Pregnant wild-type and ASIC2a+/- mice received 40 mg/kg of pentylenetetrazol (i.p.) and were video recorded for 30 min. Behaviors were scored using a modified Racine scale (0-7: 0 = no seizure; 7 = respiratory arrest/death). Seizure severity was classified as mild (score = 1-3) or severe (score = 4-7). RUPP mice had reduced hippocampal and placental ASIC2a protein. ASIC2a+/- mice had reduced latency to seizures, increased seizure duration, increased severe seizure duration, and higher maximum seizure scores. Reduced hippocampal ASIC2a in RUPP mice and increased seizure activity in pregnant ASIC2a+/- mice support the hypothesis that reduced ASIC2a increases seizure sensitivity associated with the RUPP.

Correlations of CYP11B2 gene polymorphisms with eclampsia.

OBJECTIVE: The aim of this study was to explore the relationship between CYP11B2 gene polymorphisms and eclampsia. PATIENTS AND METHODS: A total of 400 pregnant women treated in our hospital were enrolled in this study, including 200 normal pregnant women (pregnancy group) and 200 pregnant women with eclampsia (eclampsia group). Peripheral blood was collected from subjects of the two groups. Subsequently, genomic deoxyribonucleic acids (DNAs) were extracted and amplified via polymerase chain reaction (PCR) for detection of CYP11B2 rs4543, rs3802228 and rs104894072 polymorphisms. The expression level of CYP11B2 gene was measured as well. Additionally, the correlations of CYP11B2 gene polymorphisms with blood pressure and coagulation and renal function indexes were analyzed. RESULTS: The distribution of alleles of rs4543 locus in CYP11B2 gene was significantly different between eclampsia group and pregnancy group (p=0.027). The frequency of the allele C was significantly lower in eclampsia group than that of pregnancy group (p<0.05). There was a statistically significant difference in the genotype distribution of CYP11B2 rs3802228 (p=0.000) and rs104894072 (p=0.000) between eclampsia group and pregnancy group (p<0.05). Meanwhile, the frequency of AA genotype of rs3802228 and TG genotype of rs104894072 was remarkably higher in eclampsia group than that in pregnancy group (p<0.05). The distribution of the locus rs104894072 (p=0.044) in dominant model and rs3802228 (p=0.002) in recessive model in eclampsia group was different from that in pregnancy group (p<0.05). Eclampsia group showed remarkably elevated frequency of TT + TG of the locus rs104894072 in dominant model and lowered frequency of AG + GG of the locus rs3802228 in recessive model (p<0.05). Similarly, a significant difference was observed in the distribution of the haplotypes CGG (p=0.001) and TGT (p=0.048) in CYP11B2 gene between eclampsia group and pregnancy group (p<0.05). The linkage disequilibrium of the loci rs3802228 and rs104894072 was relatively high (D'=0.382). The polymorphism of the locus rs104894072 in CYP11B2 gene had an evident relation to CYP11B2 gene expression (p<0.05). Meanwhile, the expression of CYP11B2 gene was markedly higher in patients with GG genotype in eclampsia group (p<0.05). The polymorphism of CYP11B2 rs4543 was notably associated with PT level of patients in eclampsia group (p=0.000). Conversely, rs3802228 polymorphism was correlated with 24 h urine protein level (p=0.000). Besides, the proportion of patients with CGG haplotype was significantly larger among patients with systolic blood pressure of 140-160 mmHg (p<0.05). In addition, the proportion of patients with TGT haplotype was evidently greater among patients with systolic blood pressure >180 mmHg in eclampsia group (p<0.05). CONCLUSIONS: CYP11B2 gene polymorphisms are significantly correlated with the development and progression of eclampsia.

Effects of preeclampsia and eclampsia on maternal metabolic and biochemical outcomes in later life: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the association between preeclampsia (PE) and eclampsia (E) on subsequent metabolic and biochemical outcomes. METHODS: Systematic review and meta-analysis of observational studies. We searched five engines until November 2018 for studies evaluating the effects of PE/E on metabolic and biochemical outcomes after delivery. PE was defined as presence of hypertension and proteinuria at >20 weeks of pregnancy; controls did not have PE/E. Primary outcomes were blood pressure (BP), body mass index (BMI), metabolic syndrome (MetS), blood lipids and glucose levels. Random effects models were used for meta-analyses, and effects reported as risk difference (RD) or mean difference (MD) and their 95% confidence interval (CI). Subgroup analyses by time of follow up, publication year, and confounder adjustment were performed. RESULTS: We evaluated 41 cohorts including 3300 PE/E and 13,967 normotensive controls. Women were followed up from 3 months after delivery up to 32 years postpartum. In comparison to controls, PE/E significantly increased systolic BP (MD = 8.3 mmHg, 95%CI 6.8 to 9.7), diastolic BP (MD = 6.8 mmHg, 95%CI 5.6 to 8.0), BMI (MD = 2.0 kg/m2; 95%CI 1.6 to 2.4), waist (MD = 4.3 cm, 95%CI 3.1 to 5.5), waist-to-hip ratio (MD = 0.02, 95%CI 0.01 to 0.03), weight (MD = 5.1 kg, 95%CI 2.2 to 7.9), total cholesterol (MD = 4.6 mg/dL, CI 1.5 to 7.7), LDL (MD = 4.6 mg/dL; 95%CI 0.2 to 8.9), triglycerides (MD = 7.7 mg/dL, 95%CI 3.6 to 11.7), glucose (MD = 2.6 mg/dL, 95%CI 1.2 to 4.0), insulin (MD = 19.1 pmol/L, 95%CI 11.9 to 26.2), HOMA-IR index (MD = 0.7, 95%CI 0.2 to 1.2), C reactive protein (MD = 0.05 mg/dL, 95%CI 0.01 to 0.09), and the risks of hypertension (RD = 0.24, 95%CI 0.15 to 0.33) and MetS (RD = 0.11, 95%CI 0.08 to 0.15). Also, PE/E reduced HDL levels (MD = -2.15 mg/dL, 95%CI -3.46 to -0.85). Heterogeneity of effects was high for most outcomes. Risk of bias was moderate across studies. Subgroup analyses showed similar effects as main analyses. CONCLUSION: Women who had PE/E have worse metabolic and biochemical profile than those without PE/E in an intermediate to long term follow up period.

Endothelial dysfunction in pregnancy metabolic disorders.

In recent years, the vascular endothelium has gained attention as a key player in the initiation and development of pregnancy disorders. Endothelium acts as an endocrine organ that preserves the homeostatic balance by responding to changes in metabolic status. However, in metabolic disorders, endothelial cells adopt a dysfunctional function, losing their normal responsiveness. During pregnancy, several metabolic changes occur, in which endothelial function decisively participates. Similarly, when pregnancy metabolic disorders occur, endothelial dysfunction plays a key role in pathogenesis. This review outlines the main findings regarding endothelial dysfunction in three main metabolic pathological conditions observed during pregnancy: gestational diabetes, hypertensive disorders, and obesity and hyperlipidemia. Organ, histological and cellular characteristics were thoroughly described. Also, we focused in discussing the underlying molecular mechanisms involved in the cellular signaling pathways that mediate responses in these pathological conditions.

Correlation analysis between COX-2 gene polymorphism and eclampsia.

OBJECTIVE: The aim of this study was to investigate the expression of cyclooxygenase-2 (COX-2) in eclampsia patients, and to explore the correlation between COX-2 polymorphism and incidence of eclampsia. PATIENTS AND METHODS: From January 2016 to January 2018, a total of 280 pregnant women diagnosed in the Obstetrics and Gynecology Department of our hospital were selected for this study. All patients were divided into two groups, including normal pregnancy control group (n=120) and eclampsia group (n=160). The expression of COX-2 in placenta and umbilical cord tissues of eclampsia group and normal group was detected via Reverse Transcription-Polymerase Chain Reaction (RT-PCR), Western blotting and immunohistochemical staining. The single-nucleotide polymorphisms (rs1526172, rs1245231 and rs2198532) in the promoter region of the COX-2 gene were typed via conformation difference gel electrophoresis. Whether the distribution frequency of COX-2 genotypes met Hardy-Weinberg equilibrium law was detected via the Chi-square test. Meanwhile, the correlation between COX-2 alleles and gene polymorphisms and the incidence of eclampsia was analyzed. RESULTS: The messenger ribonucleic acid (mRNA) and protein expression levels of COX-2 in the eclampsia group were significantly higher than those of the normal group (p<0.05). According to the analysis, three polymorphisms of COX-2 gene were all in line with Hardy-Weinberg equilibrium distribution (p>0.05). Gene association analysis revealed that only polymorphisms (rs1526172 and rs1245231) and alleles were correlated with the incidence of eclampsia (p<0.05). However, polymorphism rs2198532 and alleles were not correlated with the incidence of eclampsia (p>0.05). CONCLUSIONS: Rs1526172 and rs1245231 in the promoter region of COX-2 are correlated with the incidence of eclampsia, while rs2198532 has no correlation with eclampsia.

Eclampsia: a neurological perspective.

Eclampsia is a poorly understood disorder characterized by seizures or unexplained coma in setting of gestational hypertension. Its neurological manifestations are varied and are an important cause of the morbidity and mortality associated. We present a comprehensive prospective study of forty women recruited over four years describing neurological symptoms and signs, neuroimaging and laboratory studies as well as prognosis including 3-6 months follow-up. The seizures occurred in the postpartum period in majority of women (55%), while 45% had seizures before labor, and the rest (5%) during labor. Interestingly, one third of the women suffered their first seizures more than 48 h postpartum (late postpartum eclampsia). A sizable minority suffered more than one seizure and some had documented partial seizures. Headache preceded seizures by more than a day and was described as throbbing or pounding pain by most. The visual symptoms in decreasing frequency were blurring, blindness, scotoma and visual processing deficits. The most common finding during the neurological exam was memory deficits, followed by increased deep tendon reflexes (asymmetric in some), visual perception deficits, visual information processing deficits, altered mental status and cranial nerve deficits. Intracranial or intraspinal pressure when examined was elevated. Among neuroimaging studies, MRI was more sensitive compared to CT scan. The MRI abnormalities included both white as well as gray matter and the most common location of abnormalities was high frontal/parietal lobe. The laboratory studies revealed proteinuria in majority, but not in all. The liver function tests were abnormal in many, while few patients had HELLP syndrome. The neurological deficits resolved by the time of discharge in all. At follow-up, some patients developed new neurological problems such as recurrent headaches or seizures.

Advances in the understanding of eclampsia.

Preeclampsia, a serious hypertensive complication of pregnancy characterized by new-onset hypertension and proteinuria after midpregnancy, is a multisystem disorder that often involves the central nervous system. Neurologic signs and symptoms include hyperreflexia, headaches, visual disturbance, seizures, and cerebral hemorrhage. Eclampsia-new-onset seizures in the setting of preeclampsia-usually occurs before or within 48 hours of delivery, but can present as late as 1 month postpartum (late postpartum eclampsia). Magnesium sulfate is the drug of choice to prevent and treat eclampsia, a recommendation validated through large, randomized, and placebo-controlled trials. This review describes the pathogenesis, clinical features, and treatment of eclampsia, focusing on recent observations regarding roles of circulating antiangiogenic factors in the pathogenesis of the neurologic complications of eclampsia.

Comparison of metabolic syndrome variables among pregnant women with and without eclampsia.

BACKGROUND: Similarities in the pathogenesis of pre-eclampsia and metabolic syndrome have been described. This study is aimed at determining whether metabolic syndrome variables occur in eclampsia. METHODS: Consecutive 45 patients with eclampsia were prospectively compared with age, gestational age and parity-matched women with uncomplicated pregnancy. The main outcome measures included plasma lipids, glucose, electrolytes and uric acid levels. RESULTS: The patients were predominantly made up of ethnic Hausa primigravidae aged 15-30 years (mean: 19.5 +/- 4.2 years). As expected, patients with eclampsia had significantly higher blood pressure than controls: (systolic 163.0 +/- 24.7 vs. 124.8 +/- 18.1 mmHg, p = 0.001; diastolic 120.8 +/- 8.7 vs. 79.6 +/- 10.7 mmHg, p = 0.001). Compared to the controls, the eclamptics also had significantly higher total plasma cholesterol (5.1 +/- 0.7 vs. 4.6 +/- 0.4 mmol/L, p = 0.001), triglyceride (1.9 +/- 0.2 vs. 1.7 +/- 0.2 mmol/L, p = 0.01), uric acid (10.4 +/- 2.7 vs. 4.4 +/- 0.8 mol/L, p = 0.005) and blood glucose (6.3 +/- 2.3 vs. 5.0 +/- 1.0 mg/dL, p = 0.01). The risk for intrapartum eclampsia was significantly increased for women with hypercholesterolemia [odds ratio (OR) = 6.9; 95% CI: 2.5-20.7] hypertriglyceridemia (OR = 5.0; 95% CI: 1.79-14.32) and hyperuricemia (OR = 35.3; 95% CI: 9.6-14.3). CONCLUSIONS: These results demonstrate that markers of metabolic syndrome also exist in this cohort of pregnant women with eclampsia and could suggest that both conditions are linked.

Neurovascular mechanisms of hypertension in pregnancy.

Normal pregnancy is associated with significant changes in the neuronal and vascular control mechanisms of blood pressure (BP). Preeclampsia (PE) is a major complication of pregnancy characterized by proteinuria, and increased vascular resistance and BP. If untreated, PE leads to eclampsia with serious seizures and severe hypertension. However, the neurovascular mechanisms of hypertension in pregnancy and PE are unclear. Studies in animal models of hypertension in pregnancy suggest that inadequate cytotrophoblast invasion of uterine spiral arteries causes reduction in uteroplacental perfusion pressure leading to placental ischemia/hypoxia. Placental ischemia may promote the release of biologically active factors such as cytokines and reactive oxygen species. These circulating factors may increase the vascular permeability, cross the blood-brain barrier, and affect the sympathetic tone and the neuronal control mechanisms of BP. Placental factors could also cause endothelial cell dysfunction and inhibit nitric oxide (NO)-cyclic guanosine monophosphate (cGMP), prostacyclin (PGI(2))-cyclic adenosine monophosphate (cAMP), and hyperpolarizing factor vascular relaxation pathways. Additionally, placental factors may induce endothelium-derived contracting factors such as endothelin, thromboxane and angiotensin II, which stimulate Ca(2+)-dependent vascular smooth muscle (VSM) contraction or increase protein kinase C activity and enhance myofilament sensitivity to intracellular free calcium concentration ([Ca(2+)](i)). The increased sympathetic tone combined with systemic decrease in endothelium-dependent vascular relaxation and enhanced VSM contraction may contribute to the increased vascular resistance and BP associated with PE. The hypertensive state in severe PE may weaken the blood-brain barrier and precipitate convulsions and cerebral hemorrhage. Careful monitoring of maternal neuronal, endothelial, and VSM function during pregnancy should circumvent the life-threatening neurovascular complications of PE-eclampsia.

[Differential expression of extracellular matrix metalloproteinase inducer in normal placenta and preeclampsia placenta].

OBJECTIVE: To study the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in preeclampsia placenta and the relation with preeclampsia attacks. METHODS: Forty-four samples from pregnant women with preeclampsia (preeclampsia group), 38 samples from pregnant women with eclampsia, and 49 samples from normal pregnancies (control group) were obtained. We detected the expression of EMMPRIN in placenta by immunohistochemistry and the expression of EMMPRIN mRNA by RT-PCR. RESULTS: (1) EMMPRIN positive expression: in preeclampsia group, the moderate expression rate was 18% (8/44) and the strong positive rate was 9% (4/44); in eclampsia group moderate positive rate was 21% (8/38) and strong positive rate 13% (5/38). The difference of the two groups was insignificant (P > 0.05). In control group the moderate positive rate was 12% (6/49) and strong positive rate 82% (40/49), the difference from the preeclampsia and the eclampsia groups was significant (P < 0.001). (2) EMMPRIN mRNA expression: in preeclampsia group EMMPRIN mRNA expression in term placenta (37 - 40 gestational weeks) was 0.342 +/- 0.002, and in eclampsia group 0.344 +/- 0.023; the difference between the two groups was insignificant (P > 0.05). In control group EMMPRIN mRNA expression in term placenta (37 - 40 gestational weeks) was 0.872 +/- 0.094, the differences between the control group and preeclampsia and eclampsia groups were both significant (P < 0.001). CONCLUSION: The decrease in the expression of EMMPRIN in placenta is an important cause of preeclampsia onset; expression rate of EMMPRIN may serve as an indicator in predicting preeclampsia.

Preeclampsia/Eclampsia candidate genes show altered methylation in maternal leukocytes of preeclamptic women at the time of delivery.

OBJECTIVE: To analyze methylation profiles of known preeclampsia/eclampsia (PE) candidate genes in normal (NL) and preeclamptic (PE) women at delivery. METHODS: A matched case-control study comparing methylation in 79 CpG sites/33 genes from an independent gene set in maternal leukocyte DNA in PE and NL (n = 14 each) on an Illumina BeadChip platform. Replication performed on second cohort (PE = 12; NL = 32). RESULTS: PE demonstrates differential methylation in POMC, AGT, CALCA, and DDAH1 compared with NL. CONCLUSION: Differential methylation in four genes associated with PE may represent a potential biomarker or an epigenetic pathophysiologic mechanism altering gene transcription.

The Contribution of Normal Pregnancy to Eclampsia.

Eclampsia, clinically defined as unexplained seizure in a woman with preeclampsia, is a life threatening complication unique to the pregnant state. However, a subpopulation of women with seemingly uncomplicated pregnancies experience de novo seizure without preeclamptic signs or symptoms, suggesting pregnancy alone may predispose the brain to seizure. Here, we hypothesized that normal pregnancy lowers seizure threshold and investigated mechanisms by which pregnancy may affect seizure susceptibility, including neuroinflammation and plasticity of gamma-aminobutyric acid type A receptor (GABAAR) subunit expression. Seizure threshold was determined by quantifying the amount of pentylenetetrazole (PTZ) required to elicit electrical seizure in Sprague Dawley rats that were either nonpregnant (Nonpreg, n = 7) or pregnant (Preg; d20, n = 6). Seizure-induced vasogenic edema was also measured. Further, activation of microglia, a measure of neuroinflammation (n = 6-8/group), and GABAAR δ- and γ2-subunit protein expression in the cerebral cortex and hippocampus (n = 6/group) was determined. Seizure threshold was lower in Preg compared to Nonpreg rats (36.7±9.6 vs. 65.0±14.5 mg/kg PTZ; p<0.01) that was associated with greater vasogenic edema formation (78.55±0.11 vs. 78.04±0.19% water; p<0.05). The % of active microglia was similar between groups; however, pregnancy was associated with downregulation of cortical GABAAR-δ and hippocampal GABAAR-γ2 expression. Overall, pregnancy appears to be a state of increased seizure susceptibility that is not due to neuroinflammation, but rather is associated with reduced expression of GABAAR subunits and greater edema. Understanding neurophysiological changes occurring in normal pregnancy could allow for better prevention and management of de novo seizure, including pathologic states such as eclampsia.

Magnesium sulfate in eclampsia and pre-eclampsia: pharmacokinetic principles.

Magnesium sulfate (MgSO4) is the agent most commonly used for treatment of eclampsia and prophylaxis of eclampsia in patients with severe pre-eclampsia. It is usually given by either the intramuscular or intravenous routes. The intramuscular regimen is most commonly a 4 g intravenous loading dose, immediately followed by 10 g intramuscularly and then by 5 g intramuscularly every 4 hours in alternating buttocks. The intravenous regimen is given as a 4 g dose, followed by a maintenance infusion of 1 to 2 g/h by controlled infusion pump. After administration, about 40% of plasma magnesium is protein bound. The unbound magnesium ion diffuses into the extravascular-extracellular space, into bone, and across the placenta and fetal membranes and into the fetus and amniotic fluid. In pregnant women, apparent volumes of distribution usually reach constant values between the third and fourth hours after administration, and range from 0.250 to 0.442 L/kg. Magnesium is almost exclusively excreted in the urine, with 90% of the dose excreted during the first 24 hours after an intravenous infusion of MgSO4. The pharmacokinetic profile of MgSO4 after intravenous administration can be described by a 2-compartment model with a rapid distribution (a) phase, followed by a relative slow beta phase of elimination. The clinical effect and toxicity of MgSO4 can be linked to its concentration in plasma. A concentration of 1.8 to 3.0 mmol/L has been suggested for treatment of eclamptic convulsions. The actual magnesium dose and concentration needed for prophylaxis has never been estimated. Maternal toxicity is rare when MgSO4 is carefully administered and monitored. The first warning of impending toxicity in the mother is loss of the patellar reflex at plasma concentrations between 3.5 and 5 mmol/L. Respiratory paralysis occurs at 5 to 6.5 mmol/L. Cardiac conduction is altered at greater than 7.5 mmol/L, and cardiac arrest can be expected when concentrations of magnesium exceed 12.5 mmol/L. Careful attention to the monitoring guidelines can prevent toxicity. Deep tendon reflexes, respiratory rate, urine output and serum concentrations are the most commonly followed variables. In this review, we will outline the currently available knowledge of the pharmacokinetics of MgSO4 and its clinical usage for women with pre-eclampsia and eclampsia.

Activin A and activin receptors in gestational tissue from preeclamptic pregnancies.

Maternal serum activin A levels are elevated in women with preeclampsia. To explore whether this could be due, at least in part, to increased production by the gestational tissues, we have measured activin A in the serum of women with (n=23) or without preeclampsia (n=62) at 29-40 weeks of gestation and in placenta and fetal membranes from preterm preeclamptic (PT-PE, n=8), term preeclamptic (T-PE, n=10) and healthy term controls (T-C, n=10). We have also explored if there are associated changes in activin receptor Alk2, ActRII and ActRIIB in these tissues. The relative amounts of receptor proteins were measured by densitometry on Western blots and receptors and activin beta(A) subunit localised by immunohistochemistry in PT-PE, T-PE and T-C gestational tissues (n=8-10/group). Maternal serum activin A levels were significantly elevated in women with preeclampsia (multiples of the normal median (MoM)=3.5, P<0.0001, Mann-Whitney U test) compared with healthy women (median MoM=1.0). Compared with control tissues, the activin A content was significantly higher in preeclamptic placentae (P=0.001 and P=0.0005 for PT-PE and T-PE respectively, Mann-Whitney U test), but significantly lower in the amnion (P=0.005 and P=0.014 for PT-PE and T-PE respectively) and choriodecidua (P=0.009 for T-PE). The maternal serum activin A level in women with preeclampsia was significantly correlated with elevated placental production (P=0.01, Pearson's correlation). Receptor Alk2 protein levels were significantly elevated in T-PE placentae (P=0.0006, Mann-Whitney U test), ActRIIB levels were significantly lower in PT-PE placentae (P=0.01) and ActRII levels were significantly lower in PT-PE choriodecidua (P=0.0002) compared with controls. There were no apparent differences in the distribution of the beta(A) subunit and receptors Alk2, ActRII and ActRIIB between control and preeclamptic tissues. These findings suggest that elevated levels of activin A in the maternal circulation in association with preeclampsia are due, at least in part, to increased placental production, and that the regulation of activin synthesis in placenta and fetal membranes is differentially regulated. Further, the differences in activin receptor protein levels between preeclamptic and control placenta and choriodecidua suggest that activin A-induced regulation may be altered in preeclampsia.

Role of prostaglandin E2 in alterations of the beta-adrenergic system from rat eclamptic uterus.

The inotropic effect of isoproterenol, as well as the beta-adrenoceptor population, was measured in pregnant uterine tissue from female spontaneous hypertensive rats (SHR) (control group: C) and female SHR that were grafted with skin from Holtzman male rats (eclamptic group: E). The Kd value of the concentration-response curve of isoproterenol was higher for uteri from E rats than C rats. This phenomenon was not accompanied by a modification in the expression of beta-adrenoceptors. Inhibition of the synthesis of prostaglandins prevented the hyporeactivity to isoproterenol during eclampsia. Moreover, uteri from E rats generated and released greater amounts of prostaglandin E2 (PGE2) than uteri from C rats, even in the presence or absence of isoproterenol. In addition, whereas isoproterenol administered alone increased basal cyclic AMP (cAMP) production from C uteri, PGE2 administered alone enhanced cAMP production in E uterine tissue. These results suggest that the decrease in beta-adrenergic response to the agonist in E rats is ascribed to PGE2 production. The abnormal reactivity to the beta-agonist could be associated with a heterologous desensitization of uterine beta-adrenoceptors exerted by PGE2 overload in uteri from E rats. These results bear directly on the regulation of uterine motility during pregnancy, since an impaired response to beta-adrenergic innervation could lead to increased uterine motility, impairing the maintenance of pregnancy.

Galactose alpha 1-3 galactose and anti-alpha galactose antibody in normal and pathological pregnancies.

The galactose alpha 1-3 galactose (Gal alpha 1-3 Gal) residue is a carbohydrate widely distributed in many non-human mammals. Since Gal alpha 1-3 Gal residues are described on the cell surface of tumor cells, we have examined the possibility of their expression on human trophoblastic cells at different stages of placental implantation and in various pregnancy-associated conditions. Using immunohistochemical methods, Gal alpha 1-3 Gal was demonstrated on interstitial and vascular trophoblast during pregnancy. For villous trophoblast, the staining disappeared in second trimester pregnancies. The density of staining for Gal alpha 1-3 Gal was increased in highly invasive trophoblast (mole and choriocarcinoma) and decreased in poorly invasive specimens (spontaneous abortion, XO monosomia). No cells displaying Gal alpha 1-3 Gal at their surface were identified in some segments of spiral arteries from pre-eclamptic women. The anti-Gal antibody titer increased in the first trimester of pregnancy and in the sera of pre-eclamptic and eclamptic patients. These findings suggest that Gal alpha 1-3 Gal residues could be considered as markers for trophoblast invasive capacity and that the binding of maternal anti-Gal antibodies to the trophoblast could contribute to limit trophoblastic invasion and thus participate to the immunological control of implantation.