Fatima Crispi

Predictive value of angiogenic factors and uterine artery Doppler for early- versus late-onset pre-eclampsia and intrauterine growth restriction

To investigate potential differences in the prediction of early‐ vs. late‐onset pre‐eclampsia and/or intrauterine growth restriction (PE/IUGR) by second‐trimester uterine artery Doppler examination, and measurement of maternal serum placental growth factor (PlGF) and soluble fms‐like tyrosine kinase 1 (sFlt1).

Cardiac dysfunction and cell damage across clinical stages of severity in growth-restricted fetuses

OBJECTIVE The purpose of this study was to assess cardiac function and cell damage in intrauterine growth-restricted (IUGR) fetuses across clinical Doppler stages of deterioration. STUDY DESIGN One hundred twenty appropriate-for-gestational-age and 81 IUGR fetuses were classified in stages 1/2/3 according umbilical artery present/absent/reversed end-diastolic blood flow, respectively. Cardiac function was assessed by modified-myocardial performance index, early-to-late diastolic filling ratios, cardiac output, and cord blood B-type natriuretic peptide; myocardial cell damage was assessed by heart fatty acid-binding protein, troponin-I, and high-sensitivity C-reactive protein. RESULTS Modified-myocardial performance index, blood B-type natriuretic peptide, and early-to-late diastolic filling ratios were increased in a stage-dependent manner in IUGR fetuses, compared with appropriate-for-gestational-age fetuses. Heart fatty acid-binding protein levels were higher in IUGR fetuses at stage 3, compared with control fetuses. Cardiac output, troponin-I, and high-sensitivity C-reactive protein did not increase in IUGR fetuses at any stage. CONCLUSION IUGR fetuses showed signs of cardiac dysfunction from early stages. Cardiac dysfunction deteriorates further with the progression of fetal compromise, together with the appearance of biochemical signs of cell damage.

Neurodevelopmental outcome in 2‐year‐old infants who were small‐for‐gestational age term fetuses with cerebral blood flow redistribution

To assess the neurodevelopmental outcome at 2 years of age of children who had been small‐for‐gestational‐age (SGA) term babies with cerebral blood flow redistribution.

Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia

Background— The exact etiology of preeclampsia is unknown, but there is growing evidence of an imbalance in angiogenic growth factors and abnormal placentation. Hydrogen sulfide (H2S), a gaseous messenger produced mainly by cystathionine &ggr;-lyase (CSE), is a proangiogenic vasodilator. We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension. Methods and Results— Plasma levels of H2S were significantly decreased in women with preeclampsia (P<0.01), which was associated with reduced placental CSE expression as determined by real-time polymerase chain reaction and immunohistochemistry. Inhibition of CSE activity by DL-propargylglycine reduced placental growth factorproduction from first-trimester (8–12 weeks gestation) human placental explants and inhibited trophoblast invasion in vitro. Knockdown of CSE in human umbilical vein endothelial cells by small-interfering RNA increased the release of soluble fms-like tyrosine kinase-1 and soluble endoglin, as assessed by enzyme-linked immunosorbent assay, whereas adenoviral-mediated CSE overexpression in human umbilical vein endothelial cells inhibited their release. Administration of DL-propargylglycine to pregnant mice induced hypertension and liver damage, promoted abnormal labyrinth vascularization in the placenta, and decreased fetal growth. Finally, a slow-releasing H2S-generating compound, GYY4137, inhibited circulating soluble fms-like tyrosine kinase-1 and soluble endoglin levels and restored fetal growth in mice that was compromised by DL-propargylglycine treatment, demonstrating that the effect of CSE inhibitor was attributable to inhibition of H2S production. Conclusions— These results imply that endogenous H2S is required for healthy placental vasculature and that a decrease in CSE/H2S activity may contribute to the pathogenesis of preeclampsia. (Circulation. 2013;127:2514-2522.)

Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism; intervention; and long-term consequences.

Background Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos. Methods Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine. Principal Findings Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype. Conclusions/Significance Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.

Cardiovascular programming in children born small for gestational age and relationship with prenatal signs of severity

OBJECTIVE The objective of the study was to evaluate cardiovascular function in children who were small-for-gestational-age (SGA) fetuses. STUDY DESIGN This was a prospective study including 100 controls and 50 children diagnosed in utero as SGA after 34 weeks subdivided into the following categories: SGA and intrauterine growth restriction (IUGR) according to the absence or presence, respectively, of weight centile less than 3 or abnormal cerebroplacental Doppler. Postnatal cardiovascular outcome was evaluated at 3-6 years of age by echocardiography, blood pressure, and carotid ultrasound. RESULTS Both SGA and IUGR presented in childhood more globular hearts, reduced longitudinal motion, and impaired relaxation with an increase in radial function. Both groups showed increased blood pressure and carotid intima-media thickness. There was a linear tendency to worse cardiovascular results in IUGR as compared with SGA. CONCLUSION Fetal cardiovascular programming occurs in SGA, regardless of Doppler and weight centile. These findings challenge the concept of constitutionally small and warrant further investigation to identify predictors of cardiovascular outcome in SGA.

Performance of a first-trimester screening of preeclampsia in a routine care low-risk setting

OBJECTIVE We sought to evaluate the effectiveness of an integrated first-trimester screening test to predict preeclampsia (PE). STUDY DESIGN A prospective cohort of singleton pregnancies underwent routine first-trimester screening from 2009 through 2011 (n = 5759). A logistic regression-based predictive model for early- and late-onset PE was constructed based on: maternal characteristics; levels of pregnancy-associated plasma protein-A and free β-human chorionic gonadotropin at 8-12 weeks; and blood pressure and uterine artery Doppler at 11.0-13.6 weeks. RESULTS Of the 5170 enrolled participants, 136 (2.6%) developed PE (early PE: 26 [0.5%]; late PE: 110 [2.1%]). At 5% and 10% false-positive rates, detection rates were 69.2% and 80.8% for early PE (area under the curve, 0.95; 95% confidence interval, 0.94-0.98) and 29.4% and 39.6% for late PE (area under the curve, 0.71; 95% confidence interval, 0.66-0.76), respectively. CONCLUSION First-trimester screening combining maternal factors with uterine artery Doppler, blood pressure, and pregnancy-associated plasma protein-A is useful to predict PE in a routine care setting.

Differential effects of intrauterine growth restriction on brain structure and development in preterm infants: a magnetic resonance imaging study.

Previous evidence suggests that preterm newborns with intrauterine growth restriction (IUGR) have specific neurostructural and neurodevelopmental anomalies, but it is unknown whether these effects persist in early childhood. We studied a sample of 18 preterm IUGR, 15 preterm AGA - born between 26 and 34 weeks of gestational age (GA) - and 15 healthy born-term infants. Infants were scanned at 12 months corrected age (CA), in a 3T scanner, without sedation. Analyses were made by automated lobar volumetry and voxel-based morphometry (VBM). The neurodevelopmental outcome was assessed in all subjects at 18 months CA with the Bayley Scale for Infant and Toddler Development, third edition. IUGR infants had reduced relative volumes for the insular and temporal lobes. According to VBM, IUGR infants had bilateral reduced gray matter (GM) in the temporal, parietal, frontal, and insular regions compared with the other groups. IUGR infants had increased white matter (WM) in temporal regions compared to the AGA group and in frontal, parietal, occipital, and insular regions compared to the term group. They also showed decreased WM in the cerebellum and a non-significant trend in the hippocampus compared to term infants. IUGR infants had reduced neurodevelopmental scores, which were positively correlated with GM in various regions. These data suggest that the IUGR induces a distinct brain pattern of structural changes that persist at 1 year of life and are associated with specific developmental difficulties.

Assisted Reproductive Technologies Are Associated With Cardiovascular Remodeling In Utero That Persists Postnatally

Background— Assisted reproductive technologies (ARTs) have been shown to be associated with general vascular dysfunction in late childhood. However, it is unknown whether cardiac remodeling is also present and if these changes already manifest in prenatal life. Our aim was to assess fetal and infant (6 months of age) cardiovascular function in ART pregnancies. Methods and Results— This prospective cohort study included 100 fetuses conceived by ART and 100 control pregnancies. ART fetuses showed signs of cardiovascular remodeling, including a more globular heart with thicker myocardial walls, decreased longitudinal function (tricuspid ring displacement in controls: median, 6.5 mm [interquartile range, 6.1–7.1 mm]; tricuspid ring displacement in ART: 5.5 mm [interquartile range, 5.1–6.1]; P<0.001), impaired relaxation, and dilated atria (atrial area in controls, 1.46 cm2 [interquartile range, 1.2–1.5 cm2]; atrial area in ART, 1.6 cm2 [interquartile range, 1.3–1.8 cm2]; P<0.001). Additionally, ART infants showed persistence of most cardiac changes and a significant increase in blood pressure and aortic intima-media thickness (systolic blood pressure in controls, 74 mm Hg [interquartile range, 67–83 mm Hg]; systolic blood pressure in ART, 83 mm Hg [interquartile range, 75–94 mm Hg]; P<0.001; aortic intima-media thickness in controls, 0.52 mm [interquartile range, 0.45–0.56 mm]; aortic intima-media thickness in ART, 0.64 mm [interquartile range, 0.62–0.67]; P<0.001). We could not demonstrate that our findings were directly caused by ART because of their association with various confounding factors, including intrauterine growth restriction or factors related to the cause of infertility. Conclusions— Children conceived by ART manifest cardiac and vascular remodeling that is present in fetal life and persists in postnatal life, suggesting opportunities for early detection and potential intervention. The underlying mechanisms and the effect of potential confounders such as growth restriction or prematurity remain to be elucidated.

Monitoring of fetuses with intrauterine growth restriction : longitudinal changes in ductus venosus and aortic isthmus flow

To explore in growth‐restricted fetuses the sequence of changes in aortic isthmus and ductus venosus blood flow in relation to other arterial Doppler parameters commonly used to evaluate fetal wellbeing.