Search

Background: Uteroplacental vascular dysfunction, characterized by diminished uterine artery (UtA) blood flow in the second trimester is a clinically useful predictor of the further development of preeclampsia, fetal growth restriction and stillbirth. Efforts to develop effective treatments to protect pregnancies with abnormal UtA Dopplers would be of significant clinical benefit for mothers and their fetuses., Objective: The aim of this pilot non randomized control study was to use pravastatin +L-arginine to improve uteroplacental haemodynamics and prevent adverse maternal and neonatal outcomes in women with abnormal Dopplers and high risk for developing adverse pregnancy outcomes., Study Design: This study was performed between 2015 and 2018. All women received primary care at OB/GYN Polyclinic Jurisic and Narodni Front University Hospital, University of Belgrade Medical School, Serbia. Approval for investigational drug use was obtained and all women gave informed consent. 10 pregnant women with a poor obstetric history that developed uteroplacental dysfunction (UtA pulsatility index (PI) above the 95th percentile and notching) at 20.5 weeks IQR [17.7-22] gave consent to be treated daily with pravastatin (40 mg) and L-arginine (1.5 g) to improve placental blood flow and pregnancy outcomes. 5 women remained untreated after diagnosis at 21 weeks [20-22] (control group). Due to presence of risk factors for pregnancy complications, close maternal and fetal monitoring was undertaken in all patients. Doppler examinations were performed to monitor changes in placental vascular resistance and fetal well-being and growth., Results: PRAV+L-arginine improved uteroplacental haemodynamics, increased fetal growth and prevented early onset preeclampsia leading to delivery close to term (delivery date: median 38 weeks, IQR[36.5-39]) and appropriate weight for gestational age compared to controls, in which placental blood flow did not improve and 2 women developed severe early onset preeclampsia. Neonates from the control group were born preterm (25 weeks IQR[23.5-25]), growth restricted and spent several months at NICU. Two neonates died due to prematurity-associated complications. PRAV+L-arginine treatment prolonged pregnancies for 4.1 months, compared to 26 days in the untreated group, preventing neonatal complications associated with prematurity. The infants are now 1-3 years old and show normal growth and development., Conclusion: This study describes the successful management with pravastatin+L-arginine of 10 pregnant patients with uteroplacental vascular dysfunction and high risk of adverse maternal and fetal outcomes. A larger study is being organized to confirm these observations., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: A previous pilot study showed that pravastatin supplementation improved pregnancy outcomes in women with obstetric antiphospholipid syndrome (OAPS) that developed placental insufficiency despite standard of care treatment low molecular weight heparin plus low dose aspirin (LMWH + LDA). In this study we investigated the mechanism behind the beneficial effects of the triple therapy LMWH + LDA + pravastatin in improving uteroplacental vascular function and reducing pregnancy complications in OAPS. We hypothesized that nitric oxide (NO) is involved in the vasculoprotective effects of the triple therapy. A mouse model of OAPS that resembles the clinical scenario was used to test this hypothesis., Methods: Eleven women with OAPS that developed preeclampsia (PE) and/or intrauterine growth restriction (IUGR) associated with uteroplacental vascular dysfunction despite treatment with LMWH + LDA participated in this study after given informed written consent. Seven women were supplemented with pravastatin at the time abnormal uterine artery Dopplers were detected and 4 remained on LMWH + LDA treatment only. Wire myography was used to identify the mechanisms underpinning the protective effects of the triple therapy in the mouse model of OAPS., Results: The triple therapy increased serum NO levels, diminished uteroplacental vessels resistance improving placental function and prolonged pregnancies compared to conventional treatment LMWH + LDA, leading to live births in women with OAPS. Comparable to the observations in women, the triple therapy protected pregnancies in OAPS-mice, increasing placental perfusion and pregnancy outcomes. A synergistic vasculoprotective effect of the triple therapy on uterine arteries and aorta was demonstrated in OAPS-mice. LMWH + LDA showed a partial protection on endothelial function. Addition of pravastatin increase eNOS synthesis, expression and activity/signaling leading to a significant increment in nitric oxide (NO) generation, resulting in improved placental vascular function and total protection of pregnancies., Conclusion: LMWH + LDA + PRAV increased serum NO levels and significantly improved placental haemodynamics and maternal and neonatal outcomes in women and mice with OAPS. A role for eNOS/NO in mediating the placental vasculoprotective effects in OAPS-mice was demonstrated, strengthening the concept that impaired NO production is a crucial mediator in the pathogenesis of OAPS and a potential target for pharmacological interventions. The efficacy of pravastatin supplementation should be confirmed in a larger clinical trial., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The increase in fetal and neonatal morbidity and mortality associated with twin pregnancies correlates with an increased risk of preterm delivery, low birth weight, and intrauterine growth restriction (IUGR). Although the pathogenesis of IUGR is unclear and thus management remains a major challenge, feto-placental blood vessels are compromised, and altered umbilical blood flow is observed. In this pilot observational study we investigated the effects of pravastatin plus l-arginine on umbilical artery (umb art) blood flow. Between 2013 and 2016, five women received daily doses l-arginine and pravastatin when an umb art pulsatility index above limits for gestational age was observed and concerns about selective growth restrictions arose. All patients showed selective absent or reversed end-diastolic umbilical artery Doppler flow (AREDV) associated with increased perinatal mortality. Pravastatin (PRAV) plus l-arginine (l-Arg) treatment diminished umb art resistance significantly and allowed pregnancy to continue. No signs of acidosis or hypoxia, normal cardiotocography tracing, normal fetal movement and fetal weight gain were observed in the twins that showed abnormal umb art Dopplers. All neonates were born around 33 weeks (median 33 weeks, IQR [31.4-33.0]), thus diminishing substantially the chances for any prematurity-associated adverse neonatal outcomes. The infants now show normal growth and development. In in vitro studies, pravastatin induced relaxation of aortic rings. Murine studies identified were performed to investigate the mechanism behind PRAV+L-Arg beneficial effects. A nitric oxide (NO)-dependent synergistic vasorelaxant effect of PRAV+L-Arg was demonstrated using aortic rings. Increased levels of placental NO and increased synthesis of eNOS in placental endothelial cells were observed in mice treated with PRAV+L-Arg compared to untreated mice and mice treated with PRAV- or L-Arg alone. This study suggests that PRAV plus L-Arg might be a good therapeutic option to improve blood flow in umbilical arteries prolonging pregnancy and improving pregnancy outcomes in twins. A RCT should be organized to confirm these results., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Preeclampsia (PE), associates with long-term increased risk for cardiovascular disease in women, suggesting that PE is not an isolated disease of pregnancy. It is not known if increased risk for long-term diseases is due to PE-specific factors or to prepregnancy renal and cardiovascular risk factors. We used a mouse model in which a WT female with normal prepregnancy health develops PE to investigate if preeclampsia causes long-term cardiovascular consequences after pregnancy for mothers and offspring. Mothers exhibited endothelial dysfunction and hypertension after PE and had glomerular injury that not only persisted but deteriorated, leading to fibrosis. Left ventricular (LV) remodeling characterized by increased collagen deposition and MMP-9 expression and enlarged cardiomyocytes were also detected after PE. Increased LV internal wall thickness and mass, increased end diastolic and end systolic volumes, and increased stroke volume were observed after PE in the mothers. Placenta-derived bioactive factors that modulate vascular function, markers of metabolic disease, vasoconstrictor isoprostane-8, and proinflammatory mediators were increased in sera during and after a preeclamptic pregnancy in the mother. Offspring of PE mice developed endothelial dysfunction, hypertension, and signs of metabolic disease. Microglia activation was increased in the neonatal brains after PE, suggesting neurogenic hypertension in offspring. Prevention of placental insufficiency with pravastatin prevented PE-associated cardiovascular complications in both mothers and offspring. In conclusion, factors that develop during PE have long-term, cardiovascular effects in the mother and offspring independent of prepregnancy risk factors.

Pre-eclampsia is a disease of pregnancy affecting 5%-8% of all pregnancies and a leading cause of maternal and fetal mortality. Despite improvements in the diagnosis, there is no effective method for prevention and treatment. While studies in women are of critical importance, investigation of pathological mechanisms in pregnant women is necessarily limited, and the ability to establish cause and effect relationships, difficult. Mouse models have been instrumental in defining pathogenic mechanisms in preeclampsia and in the identification of pravastatin as a potential treatment to prevent pregnancy complications associated with placental dysfunction. Numerous epidemiological studies provided robust evidence demonstrating that pravastatin exposure during pregnancy does not affect fetal development. In addition, pravastatin is hydrophilic and has a limited passage through the placenta, diminishing any safety concerns. Several pilot studies suggest that pravastatin may be a good option to prevent and treat preeclampsia in women. While these studies are promising, the effectiveness of pravastatin to treat preeclampsia needs to be confirmed by randomized clinical trials., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Administration of conventional antithrombotic treatment (low-dose aspirin plus low-molecular weight heparin [LDA+LMWH]) for obstetric antiphospholipid syndrome (APS) does not prevent life-threatening placenta insufficiency-associated complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR) in 20% of patients. Statins have been linked to improved pregnancy outcomes in mouse models of PE and APS, possibly due to their protective effects on endothelium. Here, we investigated the use of pravastatin in LDA+LMWH-refractory APS in patients at an increased risk of adverse pregnancy outcomes., Methods: We studied 21 pregnant women with APS who developed PE and/or IUGR during treatment with LDA+LMWH. A control group of 10 patients received only LDA+LMWH. Eleven patients received pravastatin (20 mg/d) in addition to LDA+LMWH at the onset of PE and/or IUGR. Uteroplacental blood hemodynamics, progression of PE features (hypertension and proteinuria), and fetal/neonatal outcomes were evaluated., Results: In the control group, all deliveries occurred preterm and only 6 of 11 neonates survived. Of the 6 surviving neonates, 3 showed abnormal development. Patients who received both pravastatin and LDA+LMWH exhibited increased placental blood flow and improvements in PE features. These beneficial effects were observed as early as 10 days after pravastatin treatment onset. Pravastatin treatment combined with LDA+LMWH was also associated with live births that occurred close to full term in all patients., Conclusion: The present study suggests that pravastatin may improve pregnancy outcomes in women with refractory obstetric APS when taken at the onset of PE or IUGR until the end of pregnancy.

Preterm birth (PTB) is a major public health problem, with a global prevalence of 9.6% and over a million annual neonatal deaths. In a mouse model of preterm labor (PTL) induced by intravaginal administration of a subclinical dose of lipopolysaccharide (LPS), we previously demonstrated that LPS ascends to the cervix, inducing complement activation, cervical remodeling and PTL. Here we show that complement activation also plays a role in myometrial contractions during PTL in this model. Increased levels of C5a were detected in the myometrium of LPS-treated mice but not in age-matched control or term myometrium. Human and mouse myometrium incubated with C5a showed increased frequency of contractions and expression of connexin 43, suggesting that C5a is an uterotonic molecule. Statins, which showed beneficial effects in preventing complement-mediated pregnancy complications, prevented cervical remodeling, myometrial contractions and PTL in the LPS model. The protective effects of statins in PTL were associated with increased synthesis, expression and activity of heme oxygenase (HO-1) in myometrium and cervix. Coadministration of HO-1 inhibitor tin-protoporphyrin-IX with pravastatin abrogated the protective effects of pravastatin on cervical remodeling and myometrial contractions leading to PTB. In addition, pravastatin inhibited complement activation in the cervix by increasing the synthesis and expression of complement inhibitor decay-accelerating factor. This study in mice suggests that statins might be useful to prevent PTL in humans. Clinical trials in humans are needed and if these results are confirmed, they may form the basis for a new clinical approach to prevent PTB., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Miscarriages in patients with antiphospholipid (aPL) antibodies have been attributed to thrombosis of placental vessels. However, we have shown that inflammation plays a crucial role in fetal injury. We identified tissue factor (TF), the major cellular activator of the coagulation cascade, as a key mediator in inflammation and fetal injury in aPL antibody-treated mice. We found that TF in maternal neutrophils was associated with fetal injury. TF expression in neutrophils contributes to the respiratory burst and subsequent trophoblast oxidative injury and pregnancy loss induced by aPL antibodies. We also analysed how TF contributes to neutrophil activation and trophoblast injury in this model. We showed that neutrophils from aPL antibody-treated mice express protease activated receptor 2 (PAR-2) and that stimulation of this receptor leads to neutrophil activation, trophoblast injury and fetal death. Mice deficient in PAR-2 and treated with aPL antibodies exhibited reduced neutrophil activation and normal pregnancies, indicating that PAR-2 plays an important role in the pathogenesis of aPL antibody-induced fetal injury. In addition, we demonstrated that the statins simvastatin and pravastatin downregulate TF and PAR-2 expression in neutrophils and thus prevent pregnancy loss. In summary, this study shows that TF signaling through PAR-2 mediates neutrophil activation and fetal death in antiphospholipid syndrome, and that statins may be an appropriate treatment for women with aPL antibody-induced pregnancy complications.

Pregnancy loss and intrauterine growth restriction (IUGR) are serious pregnancy complications, and the triggers and mediators of placental and fetal damage are not completely understood. Using a mouse model of recurrent spontaneous miscarriages (DBA/2-mated CBA/J mice) that shares features with human recurrent miscarriage and fetal growth restriction, we identified tissue factor (TF) as an essential participating factor in placental and fetal injury. We have previously shown that C5a releases antiangiogenic molecule sFlt-1 in monocytes that causes defective placental development and fetal death in DBA/2-mated CBA/J mice. In this study, we found that TF not only activates the coagulation pathway, but it also mediates sFlt-1 release in monocytes causing defective placental development and fetal death. Blockade of TF with a monoclonal antibody inhibited sFlt-1 release, prevented the pathological activation of the coagulation pathway, restored placental blood flow, prevented placental oxidative stress, and rescued pregnancies. We also demonstrated that pravastatin, by down-regulating TF expression on monocytes and trophoblasts, prevented placental damage and protected pregnancies in DBA/2-mated CBA/J mice. These studies indicate that TF is an important mediator in fetal death and growth restriction and that statins may be a good treatment for women with recurrent miscarriages and IUGR.