First trimester placental vascularization and angiogenetic factors are associated with adverse pregnancy outcome.

BACKGROUND: Hypertensive disorders, fetal growth restriction and preterm birth are major obstetrical complications and are related to impaired placentation. Early identification of impaired placentation can advance clinical care by preventing or postpone adverse pregnancy outcome. OBJECTIVES: Determine whether sonographic assessed placental vascular development and concomitant changes in inflammation- and/or angiogenesis-related serumproteins differ in the first trimester between uncomplicated pregnancies and pregnancies with adverse outcome. STUDY DESIGN: This prospective longitudinal study defines adverse pregnancy outcome as conditions associated with impaired placentation; fetal growth restriction, hypertensive disorder, preterm birth and placental abruption. The vascularization index, flow index, vascularization flow index and placental volume were determined at 8, 10 and 12 weeks pregnancy from 64 women using 3D power Doppler. Serum levels were analyzed for Angiopoetin-1 and -2, Leptin, VEGF-R, VEGF, and EGF. RESULTS: The vascularization index and vascular flow index increased in uneventful pregnancies with almost 50% between 8 and 12 weeks, resulting in a ∼50% higher vascularization index at 12 weeks compared to women with an adverse pregnancy outcome. Women with an adverse pregnancy outcome (n = 13) had significantly lower indices and placental volumes at all time points measured and these indices did not increase between 8 and 12 weeks. Reduced vascular development was associated with increased Angiopoietin-1 levels at 8 and 12 weeks and increased Leptin levels at 8 weeks. CONCLUSIONS: Pregnancies with an adverse outcome caused by conditions associated with impaired placentation differ from uneventful pregnancies in having reduced placental vascularization accompanied by elevated circulating levels of Angiopoietin-1 and Leptin already in the first trimester.

Early-onset preeclampsia and the prevalence of postpartum metabolic syndrome.

OBJECTIVE: To determine the prevalence of the metabolic syndrome postpartum in women with a history of pregnancy complicated by early-onset vascular disorders compared with women with late-onset disorders. METHODS: In this retrospective cohort study 849 women with a history of pregnancy complicated by vascular disorders (preeclampsia; gestational hypertension; hemolysis, elevated liver enzymes, low platelets syndrome; eclampsia; placental abruption; fetal growth restriction; and stillbirth as a result of placental insufficiency) were divided into early-onset (delivery before 32 weeks of gestation, n=376) and late-onset (delivery at or beyond 32 weeks, n=473). By use of four internationally accepted criteria to diagnose metabolic syndrome, we compared its prevalence in both groups using odds ratios (ORs), adjusted for maternal age, smoking, alcohol and coffee consumption, birth weight centile, stillbirth, and interval between delivery and measurements. RESULTS: The metabolic syndrome was present in 15-25% of women after early-onset vascular-complicated pregnancy and in 10-14% of women after late-onset disease, depending on the criteria set used; adjusted OR 2.51 (95% confidence interval [CI] 1.66-3.80) using World Health Organization criteria; adjusted OR 2.01 (95% CI 1.37-2.96) using International Diabetes Federation criteria; adjusted OR 2.16 (95% CI 1.31-3.55) using Third Adult Treatment Panel (ATPIII) criteria; and adjusted OR 2.02 (95% CI 1.28-3.17) using Third Adult Treatment Panel updated criteria. CONCLUSION: The prevalence of the metabolic syndrome postpartum is twice as high in women with a history of early-onset (delivery before 32 weeks) compared to late-onset vascular-complicated pregnancy (delivery at or beyond 32 weeks). LEVEL OF EVIDENCE: II.

Vascular expression of adrenomedullin is increased in Wistar rats during early pregnancy.

OBJECTIVE: Circulating levels of adrenomedullin (ADM)--a vasodilator peptide with long-lasting effects--increase in the course of pregnancy. Neither the site nor the concomitant rate of ADM synthesis in pregnancy is known. The aim of this study was to test the hypothesis that the rise in plasma levels of ADM during pregnancy is paralleled by increased gene expression and protein levels in the vascular bed. STUDY DESIGN: We determined in cardiovascular and reproductive tissues of non-pregnant (n=10) and 10-days pregnant (n=10) Wistar rats ADM gene expression by semi-quantitative RT-PCR (normalized to GAPDH). As a support for the mRNA data, protein concentrations were measured by both ELISA and Western blot analysis. Finally, ADM in these tissues was localized by immunohistochemical staining. Statistical analysis was carried out by applying Mann-Whitney U-test. RESULTS: ADM mRNA levels in the abdominal aorta, renal artery and the kidney were increased during pregnancy. In addition, immunohistochemical staining in the kidney, uterus, abdominal aorta, renal, uterine and superior mesenteric artery was more intense as compared to non-pregnant rats. However, we observed lower concentrations of tissue ADM protein in pregnant rats, indicating an increased release of the hormone by the producing cells. CONCLUSION: Vascular ADM gene expression is increased in the first half of rat pregnancy. This coincides and may be functionally related to the institution of a high flow/low resistance circulation in pregnancy.

PPAR gamma represses VEGF expression in human endometrial cells: implications for uterine angiogenesis.

UNLABELLED: Endometrial vasculature supports physiological uterine growth, embryonic implantation and endometrial pathology. Vascular endothelial growth factor (VEGF) is regulated by diverse developmental and hormonal signals, including eicosanoid ligands of PPARgamma. The action of natural and synthetic PPARgamma ligands on VEGF expression in primary and transformed human endometrial cell cultures was established by quantifying endogenous gene expression and transfected VEGF gene reporters. VEGF promoter-luciferase constructs were truncated and mutated to map functional sequences. Endometrial tissues and cells express PPARgamma protein. Treatment of transformed and primary endometrial cells with rosiglitazone, a synthetic PPARgamma agonist, or prostaglandin 15-deoxy-Delta12-14 J(2), a naturally occurring eicosanoid ligand, decreased VEGF protein secretion. In transiently transfected Ishikawa cells, rosiglitazone repressed VEGF gene promoter-luciferase activation with an IC(50) approximately approximately 50 nM. Truncated and mutated VEGF promoter constructs revealed that the PPARgamma-regulated domain is a direct repeat (DR)-1 motif -443 bp upstream of the transcriptional start site. CONCLUSIONS: PPARgamma ligands repress VEGF gene expression via a PPARgamma-responsive element (PPRE) in the VEGF gene promoter. Agonists of this nuclear receptor might be exploited pharmacologically to inhibit pathological vascularization in complications of pregnancy, endometriosis and endometrial adenocarcinoma.

Fetal cardiovascular response to large placental chorioangiomas.

A large placental chorioangioma is a relatively rare condition, which in 50% of all cases will lead to maternal and fetal complications. Since chorioangiomas are often associated with significant arterio-venous shunting within the placenta, several fetal hemodynamic compensatory mechanisms are initiated. Ultrasound and color Doppler flow mapping are important for the prenatal diagnosis of chorioangiomas, as an early prenatal diagnosis is crucial to minimize the risks for fetal well-being. Close surveillance of pregnancy and pregnancy termination by cesarean section at the earliest signs of fetal cardiac decompensation are indicated to reduce fetal and neonatal complications. Novel intrauterine treatment options include intravascular transfusion, fetoscopic devascularization, microcoil embolization, and intravascular injection of absolute alcohol.