Luca Marozio

Preeclamptic sera induce nephrin shedding from podocytes through endothelin-1 release by endothelial glomerular cells

In preeclampsia (PE), proteinuria has been associated with a reduced expression of nephrin by podocytes. In the present study, we investigated in vitro on human cultured podocytes the mechanism responsible for nephrin loss in PE. Sera from patients with PE did not directly downregulate the expression of nephrin. In contrast, conditioned medium obtained from glomerular endothelial cells incubated with PE sera induced loss of nephrin and synaptopodin, but not of podocin, from podocytes. Nephrin loss was related to a rapid shedding of the protein from the cell surface due to cleavage of its extracellular domain by proteases and to cytoskeleton redistribution. The absence of nephrin mRNA downregulation together with nephrin reexpression within 24 h confirm that the loss of nephrin was not related to a reduced synthesis. Studies with an endothelin-1 (ET-1) receptor antagonist that abrogated the loss of nephrin triggered by glomerular endothelial conditioned medium of PE sera indicated that ET-1 was the main effector of nephrin loss. Indeed, ET-1 was synthesized and released from glomerular endothelial cells when incubated with PE sera, and recombinant ET-1 triggered nephrin shedding from podocytes. Moreover, VEGF blockade induced ET-1 release from endothelial cells, and in turn the conditioned medium obtained triggered nephrin loss. In conclusion, the present study identifies a potential mechanism of nephrin loss in PE that may link endothelial injury with enhanced glomerular permeability.

Thrombophilia Is Significantly Associated With Severe Preeclampsia Results of a Large-Scale, Case-Controlled Study

The role of thrombophilia in the pathogenesis of preeclampsia is controversial. The aim of this case-controlled study was to determine whether thrombophilia increases the risk of preeclampsia or interferes with its clinical course. A total of 808 white patients who developed preeclampsia (cases) and 808 women with previous uneventful pregnancies (controls) matched for age and parity were evaluated for inherited and acquired thrombophilia (factor V Leiden; factor II G20210A; methylenetetrahydrofolate reductase C677T; protein S, protein C, and antithrombin III deficiency; anticardiolipin antibodies; lupus anticoagulant; and hyperhomocysteinemia). Odds ratios (ORs) with 95% confidence intervals (CIs) for risk of being carriers of thrombophilia in cases compared with controls and for risk of maternal life-threatening complications and adverse perinatal outcomes in preeclamptic patients with or without thrombophilia were calculated. Women with severe preeclampsia (406 cases) had a higher risk (OR, 4.9; 95% CI, 3.5 to 6.9) of being carriers of either an inherited or acquired thrombophilic factor, except for protein S, protein C, and antithrombin deficiency. In women with mild preeclampsia (402 cases), only prothrombin and homozygous methylenetetrahydrofolate reductase gene mutations were significantly more prevalent than in the controls. Thrombophilic patients with severe preeclampsia are at increased risk of acute renal failure (OR, 1.8; 95% CI, 1.5 to 2.2), disseminated intravascular coagulation (OR, 2.7; 95% CI, 1.1 to 6.4), abruptio placentae (OR, 2.6; 95% CI, 1.2 to 6.0) and perinatal mortality (OR, 1.7; 95% CI, 1.5 to 2.2) compared with nonthrombophilic preeclamptic patients. Our study demonstrates a significant association between maternal thrombophilia and severe preeclampsia in white women. Thrombophilia also augments the risk of life-threatening maternal complications and adverse perinatal outcomes in preeclamptic patients.

Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial

To assess whether antithrombotic prophylaxis with low-molecular-weight heparin effectively prevents recurrence of late pregnancy complications, 135 women with previous history of preeclampsia, hemolytic anemia, elevated liver enzymes and low platelet count syndrome, intrauterine fetal death, fetal growth restriction, or placental abruption who had been referred within the 12th gestational week were randomized to medical surveillance alone (n = 68) or combined to open-label nadroparin (3800 IU daily subcutaneous injections) treatment (n = 67) in the setting of a randomized, parallel-group, superiority trial, run in Italy from April 2007 to April 2010. Primary outcome was a composite end point of late-pregnancy complications. Analysis was by intention to treat. The study was stopped for futility at the time of the first planned interim analysis. Among the 128 women eventually available for final analyses, 13 of the 63 (21%) randomized to nadroparin compared with 12 of the 65 (18%) on medical surveillance alone progressed to the primary end point. The absolute event risk difference between treatment arms (2.2; -1.6 to 16.0) was not statistically significant (P = .76). Thus, nadroparin did not prevent late-pregnancy complications in women at risk of recurrence. This finding challenges the role of antithrombotic prophylaxis with low-molecular-weight heparin in the prevention of recurrent late pregnancy complications The trial was registered at http://ricerca-clinica.agenziafarmaco.it as EudraCT 2006-004205-26.

Corticotropin-releasing hormone increases prostaglandin F2α activity on human myometrium in vitro

OBJECTIVE Our purpose was to study the capability of synthetic corticotropin-releasing hormone to directly stimulate human myometrium and to modulate the activity of prostaglandins F2 alpha and E2. STUDY DESIGN Strips from human myometrium were obtained from 127 elective cesarean sections at term. The in vitro effect of human rat corticotropin-releasing hormone on myometrial contractility has been studied in resting myometrial strips mounted in a two-chamber bath for isolated organs. Stimuli (corticotropin-releasing hormone, prostaglandins F2 alpha and E2, and oxytocin) were administered as one single dose in the perfusion chamber. In each experiment one myometrial strip was used as a control. RESULTS Corticotropin-releasing hormone significantly increases (p < 0.01) the myometrial response to prostaglandin F2 alpha. The hormone neither has a direct inotropic effect nor is it able to enhance the effect of prostaglandin E2 and oxytocin on myometrial strips. CONCLUSION The positive effect of corticotropin-releasing hormone on the myometrial response to prostaglandin F2 alpha adds new support to the theory that placental corticotropins may modulate the onset of labor.

Maternal thrombophilia and the risk of recurrence of preeclampsia

OBJECTIVE The aim of this prospective study was to determine the impact of thrombophilia on the recurrence of preeclampsia. STUDY DESIGN In a multicenter, observational, cohort design, 172 white patients with a previous pregnancy complicated by preeclampsia were observed in the next pregnancy. They were evaluated for heritable thrombophilia (factor V Leiden and factor II G20210A mutations, protein S, protein C, and antithrombin deficiency), hyperhomocystinemia, lupus anticoagulant, and anticardiolipin antibodies. Development of preeclampsia and maternal complications and both gestational age at delivery and birthweight were recorded. RESULTS Sixty women (34.9%) showed the presence of a thrombophilic defect. They had a higher risk for the recurrence of preeclampsia (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.2-5.1), compared to patients without thrombophilia. Similar findings were observed considering only heritable thrombophilia. Thrombophilic patients were at increased risk for the occurrence of very early preterm delivery (< 32 weeks; OR, 11.6; 95% CI, 3.4-43.2). CONCLUSION When counseling white women with a history of preeclampsia, screening for thrombophilia can be useful for preconceptional counseling and pregnancy management.

Factor V Leiden and factor II G20210A in preeclampsia and HELLP syndrome

Background.  The association of factor V and factor II mutations with preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, and a possible role of the two thrombophilic mutations in the pathogenesis of the diseases have been previously investigated. The results, however, are still inconclusive and contradictory.

Coagulation disorders in pregnancy: acquired and inherited thrombophilias

Both acquired and inherited thrombophilias are associated with an increased risk of pregnancy‐related venous thromboembolism (VTE) as well as with adverse pregnancy outcome. However, the extension of attributable risk for each thrombophilia and outcome is still a question of debate. Thrombophilias have been investigated in connection with VTE and pregnancy complications such as: recurrent and nonrecurrent early pregnancy loss, late fetal death, placental abruption, fetal growth restriction, and preeclampsia. This review discusses the evidence of association between thrombophilias and pregnancy outcome together with issues as to clinical management and preventive strategies.

Blood pressure patterns in normal pregnancy and in pregnancy-induced hypertension, preeclampsia, and chronic hypertension

Objective To compare the 24-hour blood pressure (BP) pattern in physiologic pregnancy, pregnancy-induced hypertension, preeclampsia, and chronic hypertension. Methods We investigated four groups of women with singleton pregnancy: 73 controls, 48 patients with pregnancy-induced hypertension, 38 with preeclampsia, and 53 with mild to moderate chronic hypertension. The 24-hour BP monitoring was performed longitudinally in controls and in patients with chronic hypertension, and at the time of diagnosis in those with pregnancy-induced hypertension or preeclampsia. Results Nineteen thousand eight hundred seventy-two BP measurements were analyzed. In controls, the mean values of BP indices were lower than those first reported in nonpregnant women, and the acrophase was always localized in the first part of the afternoon. In pregnancy-induced hypertension and especially in preeclampsia, besides the obvious quantitative increase in BP, circadian BP oscillations were less pronounced than in controls, and the severity of hypertension seemed to favor the loss of diurnal rhythm. Conversely, in chronic hypertension, circadian oscillations were the same as in controls. Conclusion Standardized 24-hour BP monitoring during pregnancy allows quantitative and qualitative evaluations of the hypertensive status. However, if such a technique is used routinely in every clinical setting, we should establish specific thresholds of normality for pregnancy.

A small randomised trial of low-dose aspirin in women at high risk of pre-eclampsia

OBJECTIVE To determine if aspirin (ASA) therapy reduces the incidence of pre-eclampsia in women at high risk of this condition. STUDY DESIGN Randomised clinical trial. We recruited pregnant women with gestational age at randomisation <14 weeks, who satisfied the following criteria: chronic hypertension, history of severe pre-eclampsia or eclampsia or intrauterine growth retardation (IUGR) or intrauterine foetal death. Nineteen women in the no-treatment group and 16 in the ASA group were successfully followed up. RESULTS The mean birthweight was higher in the ASA group than in the no-treatment group (2790 g (S.D. 340 g) versus 2616 g (S.D. 779 g)), but the difference was not statistically significant. We found no statistically significant differences between the groups in the proportion of infants with birthweight below 2500 g (13.3% versus 29.4%) and the number of cases with pregnancy-induced hypertension (PIH)/pre-eclampsia (31.3% versus 36.8%). CONCLUSION These limited data give some support to the potential favourable effect of early treatment with ASA in pregnant women at risk of PIH and IUGR.

Thyroid hormones in tissues from human embryos and fetuses

This study was intended to quantify T3 and T4 in various human tissues at different stages of gestation as a contribute in the evaluation of the role of thyroid hormones in fetal development, particularly before the maturation of fetal thyroid function. Moreover, for a better comprehension of the influence of thyroid hormone status in tissues, the study was extended to adults. Embryonic specimens were obtained from voluntary abortions between 6 and 12 weeks of gestation, fetal and neonatal specimens from fetuses and neonates between 15 and 36 weeks of gestation after spontaneous abortion or stillbirth, and adult specimens from men (age range: 45–65 years) after death for cardiovascular diseases. Thyroid hormones were measured by the method of Gordon and coworkers. In embryos T3 and T4 were measured in limbs, carcasses, brain and liver: considering all values measured in the period 9–12 weeks, a mean concentration of 0.11 ng/g for T3 and 1.28 ng/g for T4 was obtained. In pooled limbs of 6–8 weeks T3 was barely measurable (0.01 ng/g). In the carcasses there was an increase in T3 and T4 concentrations of 40 and 20 times respectively from the 9th to the 12th week, when thyroid follicles oir-ganization takes place. In fetuses and adults T3 and T4 were measured in brain, heart, kidney, liver, lung, skeletal muscle and skin (mean concentrations: 0.86 ng/g for T3 and 7.44 ng/g for T4 in fetuses and neonates; 1.36 ng/g for T3 and 12.75 ng/g for T4 in adults). Hormones concentration increased with gestational age; the T3/T4 ratio increased until 22–24 weeks, when the prevalent increment in T4 occurs. T3 concentration up to 30 weeks was generally higher in tissues than in cord serum of the corresponding age. During the last month of gestation T3 increment was faster in serum. T4 level was always predominant in serum. In conclusion, T3 and T4 have been detected in the limbs of embryos before the onset of thyroid hormone secretion. Concentrations were 1/150 and 1/70, of the normal maternal blood values respectively. It is conceivable that these hormones are of maternal origin, and the question of whether such small quantities may play a role in fetal development is open.