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Importance of oxygen supply in intrauterine growth restricted (IUGR) pregnancies: correlation between in vivo and in vitro studies

Objective


Objectives:
The aim of this project is to study the role of oxygen in the pathogenesis of intrauterine growth restriction (IUGR), which represents one of the most important causes of perinatal morbidity and mortality.

Brief description:
Timing of delivery still represents the best therapy. Abnormal umbilical arterial Doppler identifies a major defect in fetoplacental perfusion and has been associated with fetal hypoxia. In pregnancies complicated by pre-eclampsia (PE) there is evidence that the placental production of the endothelium derived vasodilator nitric oxide (NO) is altered. However, biochemical and morphological findings in IUGR suggest that fetal hypoxia is due to a failure of oxygen transport through the placenta, with associated intervillous pO2 values higher than normal. Studies will be implemented for proposing models of fetal hypoxia. Comparisons will be made between in vivo 1. Indirect clinical studies of the placental circulation by Doppler waveform analysis of the umbilical and uterine arteries, and 2. direct studies of oxygen placental exchange by biochemical analysis of intervillous maternal and umbilical venous blood at the time of fetal blood sampling, and of uterine venous and umbilical venous blood at the time of cesarean section. The in vivo findings will then be associated, in the same pregnancies, to studies in vitro: 1. morphological studies of branching index of villi and vessels, proliferation patterns, expression of growth factor receptors and 2. functional studies of L-arginine transport and Na+/H+ exchange in order to establish whether there is a strong relationship between a specific placental abnormality and the clinical findings. Particular focus will be on the pathophysiology of fetal hypoxia to define whether only the fetus, the fetus and the placenta or fetus, placenta and mother are hypoxic. The studies will be performed in IUGR pregnancies, in IUGR pregnancies complicated by PE and in normal pregnancies. We will verify whether changes in the utero-placental vascularization are associated with a reduction in fetal oxygen supply and to the origin and degree of hypoxia. Moreover, comparisons will be made with the presence of morphological alterations in the placenta in different types of fetal hypoxia. In order to evaluate the advantage of possible therapeutic strategies we will also study the functional pathway of L-arginine supply, which is the precursor of placental nitric oxide production.

Keywords:
Intrauterine growth restriction; pre-eclampsia; fetal hypoxia; Doppler velocimetry; fetal blood sampling; placenta; placental transport systems; placental morphology; nitric oxide.

Funding Scheme

CON - Coordination of research actions

Coordinator

Università degli Studi di Milano
Address
Via A. Di Rudini 8
20122 Milano
Italy