Edouard Lecarpentier

Statins and Pregnancy

Cardiovascular diseases are the leading cause of mortality in industrialized countries. Treatment with statins is effective in primary prevention in patients at high cardiovascular risk. Statins are inhibitors of hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase and are classed as lipid-lowering drugs. In 2010, atorvastatin was the biggest-selling drug in the world (

Assessment of the Cervix in Pregnant Women Using Shear Wave Elastography: A Feasibility Study

US10.73 billion). Increases in the average age of pregnant women and in the prevalence of morbid obesity have inevitably led to exposure to statins in certain women during the first trimester of pregnancy. The teratogenic risk attendant upon use of statins is unclear because the available data are contradictory, but statins remain contraindicated in pregnant women.The benefits of statins in prevention of cardiovascular risk may not be solely due to their cholesterol-lowering effects: the so-called pleiotropic effects of vascular protection lead some experts to posit a potential benefit in the management of preeclampsia.In this review we evaluate the theoretical benefits and supposed risks of statins in pregnant women. After a brief overview of the pharmacodynamic properties of statins, we address the question of the teratogenic risk of statins, and then detail the rationale for the therapeutic potential of statins in preeclampsia.

Risk Factors of Superimposed Preeclampsia in Women with Essential Chronic Hypertension Treated before Pregnancy

The quantitative assessment of the cervix is crucial for the estimation of pre-term delivery risk and the prediction of the success of labor induction. We conducted a cross-sectional study using shear wave elastography based on the supersonic shear imaging technique. The shear wave speed (SWS) of the lower anterior part of the cervix was quantified over an 8-mm region of interest in 157 pregnant women. Cervical SWS is slightly but significantly reduced in patients diagnosed with pre-term labor and in patients who actually delivered pre-term.

Quantification of utero-placental vascularization in a rabbit model of IUGR with three-dimensional power Doppler angiography

Objective To determine risk factors of superimposed preeclampsia in women with essential chronic hypertension receiving antihypertensive therapy prior to conception. Methods A retrospective study of 211 patients that analyzed risk factors of superimposed preeclampsia at first prenatal visit. Variables with a p<.1 at univariate analysis were included in a logistic regression analysis. P<.05 was considered as significant. Results Superimposed preeclampsia occurred in 49 (23.2%) women. In logistic regression analysis, previous preeclampsia [OR: 4.05 (1.61–10.16)], and mean arterial blood pressure of 95 mmHg or higher [OR: 4.60 (1.94–10.93)] were associated with increased risk of superimposed preeclampsia. When both variables were present, sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratio for superimposed preeclampsia were 43%, 94%, 70%, 85%, and 7.71 (95% CI: 3.20–18.57), respectively. Conclusion In essential chronic hypertensive women, previous preeclampsia and mean arterial blood pressure of 95 mmHg or higher are associated with increased risks of superimposed preeclampsia.

Computational Fluid Dynamic Simulations of Maternal Circulation: Wall Shear Stress in the Human Placenta and Its Biological Implications.

OBJECTIVES Our objective was to evaluate the 3D power Doppler angiography (PDA) in terms of feasibility and ability to detect placental hypo-perfusion in an experimental rabbit model of intrauterine growth restriction (IUGR). STUDY DESIGN 14 pregnant females were treated with NG-nitro-L-arginine methylester (L-NAME), a nitric oxide synthase inhibitor, from day 24 to day 28 of gestation, to induce an IUGR. Concomitantly, 8 pregnant rabbits were used as controls. On day 28, 3D power Doppler indices were quantified in each utero-placental unit. Morphological examination of the placentas for the control group (n = 4) and the L-NAME group (500 mg/day, n = 4) were performed with immunohistochemical staining to discriminate the fetal capillaries in the labyrinthine area. RESULTS A total of 180 live fetuses were obtained, 108 from the L-NAME group and 72 from the control group. G28 fetal weight was significantly lower in the L-NAME group than in the control group (27.40 ± 0.55 g vs 33.14 ± 0.62 g, p < 0.0001). In the L-NAME group the vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were significantly lower than in the control group (2.6 [1.4; 6.0] vs 7.6 [3.5; 12.6], p < 0.05; 28.7 [26.5; 31.3] vs 32.9 [28.3; 38.1], p < 0.05; 0.8 [0.4; 1.8] vs 2.5 [1.1; 4.1], p < 0.05, for VI, FI and VFI, respectively). Morphological examinations revealed a substantial disorganization of the placental vascular architecture in the L-NAME group. CONCLUSION This experimental study demonstrates that quantitative 3D PDA indices are sensitive enough to detect placental vascular insufficiency in an experimental rabbit model of IUGR.

Aspirin for Prevention of Preeclampsia

Introduction In the human placenta the maternal blood circulates in the intervillous space (IVS). The syncytiotrophoblast (STB) is in direct contact with maternal blood. The wall shear stress (WSS) exerted by the maternal blood flow on the STB has not been evaluated. Our objective was to determine the physiological WSS exerted on the surface of the STB during the third trimester of pregnancy. Material and Methods To gain insight into the shear stress levels that the STB is expected to experience in vivo, we have formulated three different computational models of varying levels of complexity that reflect different physical representations of the IVS. Computations of the flow fields in all models were performed using the CFD module of the finite element code COMSOL Multiphysics 4.4. The mean velocity of maternal blood in the IVS during the third trimester was measured in vivo with dynamic MRI (0.94±0.14 mm.s-1). To investigate if the in silico results are consistent with physiological observations, we studied the cytoadhesion of human parasitized (Plasmodium falciparum) erythrocytes to primary human STB cultures, in flow conditions with different WSS values. Results The WSS applied to the STB is highly heterogeneous in the IVS. The estimated average values are relatively low (0.5±0.2 to 2.3±1.1 dyn.cm-2). The increase of WSS from 0.15 to 5 dyn.cm-2 was associated with a significant decrease of infected erythrocyte cytoadhesion. No cytoadhesion of infected erythrocytes was observed above 5 dyn.cm-2 applied for one hour. Conclusion Our study provides for the first time a WSS estimation in the maternal placental circulation. In spite of high maternal blood flow rates, the average WSS applied at the surface of the chorionic villi is low (<5 dyn.cm-2). These results provide the basis for future physiologically-relevant in vitro studies of the biological effects of WSS on the STB.

Angiogenic balance (sFlt-1/PlGF) and preeclampsia.

Aspirin is currently the most widely prescribed treatment in the prevention of cardiovascular complications. The indications for the use of aspirin during pregnancy are, however, the subject of much controversy. Since the first evidence of the obstetric efficacy of aspirin in 1985, numerous studies have tried to determine the effect of low-dose aspirin on the incidence of preeclampsia, with very controversial results. Large meta-analyses including individual patient data have demonstrated that aspirin is effective in preventing preeclampsia in high-risk patients, mainly those with a history of preeclampsia. However, guidelines regarding the usage of aspirin to prevent preeclampsia differ considerably from one country to another. Screening modalities, target population, and aspirin dosage are still a matter of debate. In this review, we report the pharmacodynamics of aspirin, its main effects according to dosage and gestational age, and the evidence-based indications for primary and secondary prevention of preeclampsia.

Discriminative imaging of maternal and fetal blood flow within the placenta using ultrafast ultrasound

Preeclampsia is a hypertensive disorder of pregnancy associated with important maternal and perinatal mortality and morbidity. Although symptomatic management has improved, there is currently no curative treatment, and only childbirth and delivery of the placenta, usually prematurely, alleviate the mothers symptoms. Placental insufficiency plays a central role in the pathophysiology of preeclampsia. Abnormal placentation during the first trimester leads to defective remodeling of the uterine vascularization. This results progressively in placental hypoperfusion, which induces trophoblast dysfunction and the release in maternal circulation of trophoblastic factors leading to an excessive inflammatory response, endothelial dysfunction and glomerular damage. Among these factors, the most important is sFlt-1, which is a soluble form of the VEGF and PlGF receptor. sFlt-1 binds to free VEGF and PlGF in the maternal circulation, thus reducing their bioavailability for their membrane receptor. The result is inhibition of the effects of VEGF and PlGF on maternal endothelial cells and podocytes. The sFlt-1/PlGF ratio reflects the circulating angiogenic balance and is correlated with severity of the disease.

Ultraslow myosin molecular motors of placental contractile stem villi in humans.

Being able to map accurately placental blood flow in clinics could have major implications in the diagnosis and follow-up of pregnancy complications such as intrauterine growth restriction (IUGR). Moreover, the impact of such an imaging modality for a better diagnosis of placental dysfunction would require to solve the unsolved problem of discriminating the strongly intricated maternal and fetal vascular networks. However, no current imaging modality allows both to achieve sufficient sensitivity and selectivity to tell these entangled flows apart. Although ultrasound imaging would be the clinical modality of choice for such a problem, conventional Doppler echography both lacks of sensibility to detect and map the placenta microvascularization and a concept to discriminate both entangled flows. In this work, we propose to use an ultrafast Doppler imaging approach both to map with an enhanced sensitivity the small vessels of the placenta (~100 μm) and to assess the variation of the Doppler frequency simultaneously in all pixels of the image within a cardiac cycle. This approach is evaluated in vivo in the placenta of pregnant rabbits: By studying the local flow pulsatility pixel per pixel, it becomes possible to separate maternal and fetal blood in 2D from their pulsatile behavior. Significance Statement: The in vivo ability to image and discriminate maternal and fetal blood flow within the placenta is an unsolved problem which could improve the diagnosis of pregnancy complications such as intrauterine growth restriction or preeclampsia. To date, no imaging modality has both sufficient sensitivity and selectivity to discriminate these intimately entangled flows. We demonstrate that Ultrafast Doppler ultrasound method with a frame rate 100x faster than conventional imaging solves this issue. It permits the mapping of small vessels of the placenta (~100 μm) in 2D with an enhanced sensitivity. By assessing pixel-per-pixel pulsatility within single cardiac cycles, it achieves maternal and fetal blood flow discrimination.

Analysis of placental vascularization in a pharmacological rabbit model of IUGR induced by l-NAME, a nitric oxide synthase inhibitor

Human placental stem villi (PSV) present contractile properties. In vitro mechanics were investigated in 40 human PSV. Contraction of PSV was induced by both KCl exposure (n = 20) and electrical tetanic stimulation (n = 20). Isotonic contractions were registered at several load levels ranging from zero-load up to isometric load. The tension-velocity relationship was found to be hyperbolic. This made it possible to apply the A. Huxley formalism for determining the rate constants for myosin cross-bridge (CB) attachment and detachment, CB single force, catalytic constant, myosin content, and maximum myosin ATPase activity. These molecular characteristics of myosin CBs did not differ under either KCl exposure or tetanus. A comparative approach was established from studies previously published in the literature and driven by mean of a similar method. As compared to that described in mammalian striated muscles, we showed that in human PSV, myosin CB rate constants for attachment and detachment were about 103 times lower whereas myosin ATPase activity was 105 times lower. Up to now, CB kinetics of contractile cells arranged along the long axis of the placental sheath appeared to be the slowest ever observed in any mammalian contractile tissue.