Cardiorenal disease following fetal growth restriction : Prevention starts in utero

Abstract

Fetal growth restriction is a condition in which the foetus can not reach its growth potential. It is mostly caused by poor placentation in which reduced oxygen and nutrients reach the fetus. Fetal growth restriction is associated with increased risk of cardiovascular and renal disease in adulthood.

In this thesis we investigate 1) which underlying mechanisms lead to this increased risk in adulthood and who is most at risk; 2) whether we can prevent or reduce this risk of cardiovascular and renal disease with treatment during pregnancy.

Part 1: In this thesis we found that fetal growth restriction leads to higher blood pressure in later life. The oxygen levels in the kidneys are also increased due to possibly less oxygen consumption of the kidneys in newborns who had suffered fetal growth restriction. This measuring method could be used to detect infants at risk for kidney disease at an early stage and then provide timely treatment to prevent both kidney disease and elevated blood pressure. We have also found a number of changes in gene expression in umbilical cord cells. These differences may be related to cardiovascular disease and abnormal kidney development. These differences could serve as a starting point for future treatments.

Part 2: Various drugs have been devised over the years that could potentially improve fetal growth and thus reduce the risk of cardiovascular disease and kidney disease. A promising drug that we have tested in this thesis is Sildenafil. Sildenafil induces vasodilation in the placenta, allowing more oxygen and nutrients towards the fetus. In a meta-analysis we show that it reduces the maternal blood pressure and increases birthweight. In an animal experiment, we observed that administration of sildenafil during pregnancies complicated with fetal growth retardation leads to higher birth weight and lower blood pressure. However, in a human study, we found no improvement in neonatal oxygen levels in the newborns and no effects on gene expression in umbilical cord or placenta cells. This difference between animals and humans may be explained by a lower dose in humans.