Development of hypertension and uraemia after pyelonephritis in childhood: 27 year follow up.

OBJECTIVE--Determination of the long term incidence of uraemia, hypertension, and toxaemia in pregnancy associated with non-obstructive focal renal scarring after pyelonephritis in childhood 25-35 years earlier. DESIGN--27 Year follow up of patients with non-obstructive focal scarring identified from a retrospective review of intravenous urograms performed in childhood between 1951 and 1967. SETTING--Paediatric primary referral centre and urological clinic in tertiary referral centre. PATIENTS--30 Patients (mean age 33 (range 22-41] with non-obstructive focal renal scarring first detected between 1951 and 1967 and a history of febrile urinary tract infection. MAIN OUTCOME MEASURE--Hypertension and complications of renal damage. RESULTS--Three patients had developed end stage renal disease, seven had developed hypertension, two of 16 women had a history of toxaemia during pregnancy, and seven patients had undergone renal surgery during follow up. Of the 20 patients who had neither had renal surgery nor had end stage renal disease, all had a significantly lower glomerular filtration rate and renal plasma flow and higher diastolic blood pressure, mean arterial blood pressure, plasma renin activity, and serum beta 2 microglobulin concentration than 13 healthy age matched controls. Diastolic blood pressure and plasma renin activity were positively correlated (r = 0.50, p less than 0.05) and so were fractional sodium excretion and both systolic and diastolic blood pressures (r = 0.54, p less than 0.01, r = 0.51, p less than 0.01 respectively). The progress of renal damage was unrelated to the incidence of recurrent infections. CONCLUSIONS--Children with focal renal scarring due to pyelonephritis are at high risk of serious long term consequences. It is essential that they are given adequate attention and care during adolescence and pregnancy.     

Central venous concentrations of immunoreactive prostaglandins E,F, and 6-keto-prostaglandin F1 in eclampsia.

Concentrations of prostaglandins E, F, and 6-keto-prostaglandin F1 alpha were estimated in central venous blood and amniotic fluid in 21 women with eclampsia and 16 healthy pregnant controls. Central venous blood concentrations of 6-keto-prostaglandin F1 alpha and prostaglandin E were significantly lower in patients than controls before delivery and remained reduced for at least 48 hours after delivery. Low concentrations of prostaglandins E and 6-keto-prostaglandin F1 alpha are probably directly related to the pathogenesis of eclampsia.     

Pre-eclampsia – a disease of oxidative stress resulting from the catabolism of DNA (primarily fetal) to uric acid by xanthine oxidase in the maternal liver: A hypothesis

Pre-eclamptic toxaemia or toxaemia has become outdated terminology for the disease of pregnancy called pre-eclampsia (PE) but, according to this hypothesis, these may be more relevant. This hypothesis is that PE is a toxaemia or poisoning of the blood that results in multi-organ dysfunction and injury, putting at risk the lives of both the infant and the mother. Yet these dysfunctions and injuries are reversible with the cessation of the pregnancy and the disease can be reduced with vitamins (antioxidants) and aspirin.This hypothesis is that the PE cascade starts with excessive shedding/embolisation of trophoblast from the placenta into the maternal venous circulation. This trophoblast embolisation (‘deportation’) is secondary either to an excessively large amount of trophoblast tissue (‘hyperplacentosis’) or to vascular trophoblast injury from a faulty uteroplacental circulation. The deported nuclear rich trophoblast is largely filtered out of the circulation in the lungs, and breaks down releasing fetal DNA. Accordingly, the level of fetal DNA in the maternal circulation rises. This DNA is then broken down in the maternal liver with the hepatocytes being presented with excessive amounts of purines for catabolism. In the hepatocytes of patients who subsequently develop PE, there is activation of xanthine oxidase (XO), the more toxic isoenzyme of xanthine oxidoreductase (XOR), with the generation of superoxide anion (O₂⁻) as a by-product. Excessive superoxide production overwhelms the normal antioxidant ability of the tissues to produce oxidative stress.In the hepatocytes, the excessive superoxide causes the peroxidation of polyunsaturated lipids to form microvesicular fat deposition. Excessive superoxide also causes hepatocellular damage with leakage of enzymes, lipids, DNA and superoxide into the circulation. In the circulation, oxidative injury of the blood corpuscles occurs releasing more DNA and accelerating purine catabolism and oxidative stress.The toxins, superoxide and the other reactive oxygen species (ROS), then travel in the arterial blood to the peripheral circulation where the microvasculature, the arterioles, capillaries, endothelial cells and venules, is injured. The damaged microvasculature leaks intravascular fluid into the extravascular compartment causing an intravascular dehydration and tissue oedema. In the kidneys, protein leaks through the damaged glomerular capillaries causing proteinuria. ROS causes arteriolar vasospasm and impairs vasorelaxation, mechanisms of hypertension. Micro-haemorrhages can occur and in the brain these, in combination with hypertension and oedema, can result in seizures or eclampsia.     

Increased immortalization‐upregulated protein 2 (IMUP‐2) by hypoxia induces apoptosis of the trophoblast and pre‐eclampsia

In regulation of the developmental process, the balance between cellular proliferation and cell death is critical. Placental development tightly controls this mechanism, and increased apoptosis of placental trophoblasts can cause a variety of gynecological diseases. Members of the immortalization‐upregulated protein (IMUP) family are nuclear proteins implicated in SV40‐mediated immortalization and cellular proliferation; however, the mechanisms by which their expression is regulated in placental development are still unknown. We compared IMUP‐2 expression in normal and pre‐eclamptic placental tissues and evaluated the function of IMUP‐2 in HTR‐8/SVneo trophoblast cells under hypoxic conditions. IMUP‐2 was expressed in syncytiotrophoblasts and syncytial knots of the placental villi. IMUP‐2 expression was significantly higher in preterm pre‐eclampsia patients than in patients who went to term (P < 0.001); however, we observed no differences in IMUP‐2 expression between normal term patients with and without pre‐eclampsia. Hypoxic conditions increased apoptosis of HTR8/SVneo trophoblast cells and induced IMUP‐2 expression. Also, apoptosis of HTR‐8/SVneo trophoblast cells was increased after IMUP‐2 gene transfection. These results suggest that IMUP‐2 expression is specifically elevated in preterm pre‐eclampsia and under hypoxic conditions, and that IMUP‐2 induces apoptosis of the trophoblast. Therefore, IMUP‐2 might have functional involvement in placental development and gynecological diseases such as pre‐eclampsia. J. Cell. Biochem. 110: 522–530, 2010. © 2010 Wiley‐Liss, Inc.     

Fibrinolysis in Pre-eclamptic Toxaemia of Pregnancy

Plasma fibrinolysis is much reduced in normal pregnancy but is the same in women with toxaemia or hypertension, though urinary fibrinolysis is lower in them. The evidence suggests that in toxaemia there must be in addition a slow state of intravascular coagulation. Fibrinolytic inhibitors were found to be normal in this series, though in pregnancy there are raised levels of antitrypsin, α₂-macroglobulin, and β-lipoprotein. β-Lipoprotein levels in non-pregnant patients show a correlation with euglobulin lysis times and with inhibitor units.     

Glucose turnover and hepatocyte glucose production of starved and toxaemic pregnant sheep

Ewes bearing twins were starved for 10 days during the last month of gestation to induce ovine pregnancy toxaemia (OPT). Glucose turnover was measured by a primed continuous infusion of [U-14C]- and [6-3H]glucose at the end of 10 days of starvation (non-susceptible), or earlier when ewes became recumbent with OPT (susceptible). All ewes were slaughtered at the end of the infusion and hepatocytes were prepared in order to measure glucose production from different substrates. Many of the ewes had dead foetuses when slaughtered. Glucose production rates by hepatocytes with the substrates propionate, lactate or alanine were significantly less from the susceptible ewes than were those from non-susceptible ewes. These low rates were not stimulated by incubation with glucagon (10(-8) M), glutamine or glycerol. Rates of glucose turnover and of hepatic glucose production from all substrates were higher for ewes with dead than with live foetuses. The data support the hypothesis that pathogenesis of OPT is related to an impairment of hepatic gluconeogenesis, and further suggest that, in starved pregnant ewes, maternal glucose production may be restrained in the presence of a live foetus.     

The Burden of Eclampsia: Results from a Multicenter Study on Surveillance of Severe Maternal Morbidity in Brazil

Objective

Maternal mortality (MM) is a core indicator of disparities in women’s rights. The study of Near Miss cases is strategic to identifying the breakdowns in obstetrical care. In absolute numbers, both MM and occurrence of eclampsia are rare events. We aim to assess the obstetric care indicators and main predictors for severe maternal outcome from eclampsia (SMO: maternal death plus maternal near miss).

Methods

Secondary analysis of a multicenter, cross-sectional study, including 27 centers from all geographic regions of Brazil, from 2009 to 2010. 426 cases of eclampsia were identified and classified according to the outcomes: SMO and non-SMO. We classified facilities as coming from low- and high-income regions and calculated the WHO’s obstetric health indicators. SPSS and Stata softwares were used to calculate the prevalence ratios (PR) and respective 95% confidence interval (CI) to assess maternal characteristics, clinical and obstetrical history, and access to health services as predictors for SMO, subsequently correlating them with the corresponding perinatal outcomes, also applying multiple regression analysis (adjusted for cluster effect).

Results

Prevalence of and mortality indexes for eclampsia in higher and lower income regions were 0.2%/0.8% and 8.1%/22%, respectively. Difficulties in access to health care showed that ICU admission (_adjPR 3.61; 95% CI 1.77–7.35) and inadequate monitoring (_adjPR 2.31; 95% CI 1.48–3.59) were associated with SMO.

Conclusions

Morbidity and mortality associated with eclampsia were high in Brazil, especially in lower income regions. Promoting quality maternal health care and improving the availability of obstetric emergency care are essential actions to relieve the burden of eclampsia.     

Could circRNA be a new biomarker for pre‐eclampsia?

Pre‐eclampsia is a devastating complication of pregnancy which is characterized by hypertension and proteinuria in pregnant women. Pre‐eclampsia is important as it is the leading cause of death. Moreover, untreated pre‐eclampsia might lead to other lethal complications, for both fetus and mother. Pre‐eclampsia can also affect the quality of life in affected women. Despite a large number of risk factors for pre‐eclampsia, these risk factors are able to detect just 30% of women who are susceptible to pre‐eclampsia. Heterogeneous manifestations of pre‐eclampsia necessitate the discovery of potential biomarkers required for its early detection. Circular RNAs (circRNAs) are a type of RNA which are more abundant, specific, and highly organized compared with other types of RNA. Accordingly, circRNAs have been suggested as one of the potential biomarkers for different diseases. Recently, researchers have shown interest in the effects of circRNAs in pre‐eclampsia, although the current evidence is limited. The majority of obstetricians are probably not aware of circRNAs as a useful biomarker. Here, we aimed to summarize recent supporting evidence and assess the mechanisms by which circRNAs are involved in pre‐eclampsia.     

Twin and singleton births in Ghana--a case-control study.

A retrospective study involving 623 twin and 1246 singleton births was conducted to compare the two groups with regard to selected maternal, fetal and labor and delivery characteristics and outcomes. Maternal age and parity were significantly higher for twins. The risks of preterm delivery, arrival in the labor ward in second stage of labor, cesarean births and postpartum haemorrhage were significantly higher in twin than in singleton births. In vaginal deliveries twin mothers were significantly less likely to have had episiotomies or perineal lacerations. There was no difference in the duration of the third stage of labor or in the incidence of retained placentae. Antepartum haemorrhage was a less likely indication for cesarean delivery among twins, while there was no significant difference in the likelihood of severe pre-eclampsia/eclampsia being an indication. Singleton babies were significantly heavier than twins. The incidences of malpresentation, low birth weight, stillbirths and of admission of live births to the neonatal intensive care unit were significantly higher in twins. There was no difference in the rate of instrumental vaginal delivery, or in the route of delivery of fetuses presenting by the breech. There is the need for detailed study of the incidences of antepartum haemorrhage and hypertensive diseases in twin and singleton pregnancies and of the factors determining the mode of delivery when such complications arise. Labor and delivery should also be examined to determine any differences between the two groups, especially in the first and second stages.     

C3 allotypes in pregnancy hypertension and eclampsia

C3 allotyping has been performed on 424 Australian women, 203 with normotensive pregnancies, 161 with hypertensive noneclamptic pregnancies and 60 eclamptic women. The frequency of women heterozygous for 'rare' C3 alleles was 1% in the normotensive women and 3.7% in the hypertensive group. Three out of 25 (12%) of the women with proteinuric hypertension in pregnancy carried 'rare' C3 alleles. This suggested the hypothesis that pre-eclampsia/eclampsia is associated with a higher frequency of rare alleles. The sample of 60 eclamptic women collected to test the hypothesis had no rare alleles, refuting the hypothesis. The frequency of the common (C3F, C3S) alleles did not differ significantly between the three groups. We conclude that there is no evidence for any association between susceptibility to eclampsia and allotypes of the C3 complement component.     

Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners' oral contraception study.

To determine the pattern of risk factors for acute myocardial infarction associated solely with women a nested case-control study was carried out on cohort data collected during the Royal College of General Practitioners'' oral contraception study. Smoking (adjusted relative risk 1.7 for light smokers and 4.3 for heavy smokers), hypertension (2.4), toxaemia of pregnancy (2.8), and diabetes mellitus (6.9) were associated with a significantly increased risk of myocardial infarction. There was no significant trend of risk with social class. Current use of the pill increased the risk only among women who also smoked (relative risk 20.8 for heavy smokers). Previous use of the pill did not influence the risk of myocardial infarction. If heavy smokers also had a history of toxaemia of pregnancy their risk of myocardial infarction was further increased (relative risk 41.0). Other variables associated solely with women, such as parity, hysterectomy, and hormone replacement therapy, had little effect on the risk of having a myocardial infarction. Overall, smoking was the most important independent risk factor and had a strong influence on risks associated with other factors.     

Salinity in Drinking Water and the Risk of (Pre)Eclampsia and Gestational Hypertension in Coastal Bangladesh: A Case-Control Study

Background

Hypertensive disorders in pregnancy are among the leading causes of maternal and perinatal death in low-income countries, but the aetiology remains unclear. We investigated the relationship between salinity in drinking water and the risk of (pre)eclampsia and gestational hypertension in a coastal community.

Methods

A population-based case-control study was conducted in Dacope, Bangladesh among 202 pregnant women with (pre)eclampsia or gestational hypertension, enrolled from the community served by the Upazilla Health Complex, Dacope and 1,006 matched controls from the same area. Epidemiological and clinical data were obtained from all participants. Urinary sodium and sodium levels in drinking water were measured. Logistic regression was used to calculate odds ratios, and 95% confidence intervals.

Findings

Drinking water sources had exceptionally high sodium levels (mean 516.6 mg/L, S.D 524.2). Women consuming tube-well (groundwater) were at a higher disease risk than rainwater users (p<0.001). Adjusted risks for (pre)eclampsia and gestational hypertension considered together increased in a dose-response manner for increasing sodium concentrations (300.01–600 mg/L, 600.1–900 mg/L, >900.01 mg/L, compared to <300 mg/L) in drinking water (ORs 3.30 [95% CI 2.00–5.51], 4.40 [2.70–7.25] and 5.48 [3.30–9.11] (p-trend<0.001). Significant associations were seen for both (pre)eclampsia and gestational hypertension separately.

Interpretation

Salinity in drinking water is associated with increased risk of (pre)eclampsia and gestational hypertension in this population. Given that coastal populations in countries such as Bangladesh are confronted with high salinity exposure, which is predicted to further increase as a result of sea level rise and other environmental influences, it is imperative to develop and evaluate affordable approaches to providing water with low salt content.     

Glucose tolerance in ewes and susceptibility to pregnancy toxaemia

Intravenous glucose tolerance tests were undertaken on fed twin-pregnant ewes at about 120 days of gestation by injecting 0.4 g glucose per kilogram of live weight, then measuring glucose and insulin concentrations in plasma over the next 2 h. An insulin resistance index was calculated from the product of T1/2 for glucose disappearance and the plasma insulin concentrations integrated over time. Approximately 10 days later, the ewes were starved to induce ovine pregnancy toxaemia. During this period, the course of the hypoglycaemia and ketonaemia were followed by measuring metabolite concentrations in jugular blood samples obtained every 2-3 days. The existence of dehydration, acid-base imbalance and renal failure was also determined from packed cell volumes, serum CO2 content and serum concentrations of urea, creatinine and inorganic phosphate. Ewes that became recumbent and moribund with the disease were classified as susceptible whereas those asymptomatic after 10 days were classified as non-susceptible. Seven susceptible ewes had significantly higher insulin resistance indices (2043 +/- 670 s.d.) than did six non-susceptible ewes (1261 +/- 433 s.d.). It was concluded that poor control of glucose homeostasis may be an important predisposing factor in pathogenesis of the disease.     

Studies of Carbohydrate and Lipid Metabolism in Women Developing Hypertension on Oral Contraceptives

Metabolic studies in 100 women developing hypertension on combined oestrogen-progestogen oral contraceptives have been compared with similar studies in normotensive women on oral contraceptives, matched for age and duration of contraceptive use, and in women not taking contraceptives.The metabolic changes known to be induced by oral contraceptives—impaired glucose tolerance, elevated blood pyruvate levels, and raised serum lipid concentrations—were found to be exaggerated in the matched hypertensive group, largely due to pronounced abnormalities in 33 subjects with diastolic blood pressures over 110 mm Hg.Women developing severe hypertension were older, more obese, and of higher parity than those with mild hypertension and there was a high incidence of previous toxaemia of pregnancy in the hypertensive group.The results show that in women on oral contraceptives changes in blood pressure and in metabolic functions tend to be correlated with one another, and are consistent with the hypothesis that oral contraception induces a primary biochemical effect whose expression in the individual is determined by intrinsic factors including genetic constitution, age, weight, and parity.     

Pre-eclampsia in pregnancies by different fathers: immunological studies.

Immunological studies were performed on a woman with severe pre-eclamptic toxaemia in a second pregnancy. This pregnancy followed a normal twin pregnancy by a different father four years earlier. Both fathers were also studied. In the mixed lymphocyte culture the patient''s lymphocytes reacted eight times as strongly against father 2''s cells as against those from father 1. If studies along these lines are performed when a women has toxaemic and non-toxaemic pregnancies by different fathers information may be obtained on immunogenetic aetiological factors which may be of more value than that derived from the study of large unselected populations.     

Fibrin Degradation Products in Normal and Abnormal Pregnancy and Parturition

The levels of fibrin, fibrinogen degradation products (F.D.P.) in the serum were investigated in normal pregnancy and parturition, after caesarean section, and in patients with abruptio placentae, eclampsia, intrauterine death, and post-partum haemorrhage. No significant change occurred during normal pregnancy, but a highly significant increase was found during labour and again during the first week after normal delivery. After caesarean section the levels of F.D.P. were increased two to four hours after operation, and substantially higher levels were found three to eight days after operation than after normal delivery. High levels of F.D.P. were associated with abruptio placentae and eclampsia, and increased levels after intrauterine death and post-partum haemorrhage.An excess of F.D.P. with diminished or normal systemic fibrinolytic activity suggests that local intravascular fibrin deposition and fibrinolysis occur in normal parturition and in these complications of pregnancy. The very high levels of F.D.P. found in abruptio placentae will be important in the pathogenesis of the defective haemostasis that may accompany this complication.     

Perinatal mortality and morbidity associated with eclampsia.

Out of all the women who were delivered in Cardiff maternity units during 1965-74, 43 developed eclampsia, an incidence of 72/100 000 deliveries. The incidence in residents of Cardiff was 53/100 000 deliveries. None of the mothers with eclampsia died, but 10 of the 47 babies were lost, all but one having been born to women with antepartum eclampsia. The perinatal deaths were mainly associated with chronic placental insufficiency and preterm delivery. The extent to which the wide range of complex drug regimens used influenced perinatal outcome is not clear, although polypharmacy should be avoided. Because eclampsia is rare we advocate that its management should be planned and rehearsed and that a simple, standardised treatment regimen should be used. Failing placental function may be detected by monitoring fetal growth by ultrasound.