Preeclampsia and the Development and Programming of Maternal and Newborn Tissues : Clinical and Epigenetic Studies

Evidence is accumulating that mothers and offspring exposed to pregnancies complicated by preeclampsia (PE) have an enhanced risk to develop cardiovascular disease in later life. According to the moment of disease-onset, two main disease entities have been identified, with early-onset PE (EOPE) as the more severe phenotype, diagnosed before 34 weeks of gestation and late-onset PE (LOPE) diagnosed at or after 34 weeks of gestation.

The adverse prenatal PE environment, characterized by intrauterine exposure to excessive oxidative stress, may disturb the development and programming of placental and newborn cardiovascular tissues, resulting in a cardiovascular phenotype of the newborn that is more susceptible to develop future cardiovascular diseases. The process of developmental programming is strongly mediated by various epigenetic mechanisms, such as DNA methylation.

The aim of this thesis was to gain more insight into the following topics: I. The development of placental and newborn cardiovascular tissues in association with EOPE and LOPE, and of the maternal microcirculation in association with PE (Part I) II. The tissue-specific DNA methylation in placental and newborn cardiovascular tissues in association with EOPE and LOPE (Part II).

The majority of data described in this thesis was obtained from a nested case-control study embedded in The Rotterdam Periconceptional Cohort, a prospective hospital-based cohort study.

Results Part I:

• EOPE was associated with a four to sevenfold decreased neutrophil count and a fivefold increased nucleated red blood cell count in umbilical cord blood (chapter 2);
• PE was associated with a smaller umbilical cord vein wall thickness and LOPE with a larger placental width (chapter 3);
• Women with severe PE and HELLP syndrome showed a reduced perfused vessel density, a reduced flow velocity and increased heterogeneity of flow in capillaries, compared with women with severe PE without HELLP syndrome (chapter 4).

Results Part II:

• DNA methylation of imprinted IGF2/H19 genes showed tissue-specific differences in Wharton jelly of the umbilical cord and placental tissue, versus umbilical cord blood mononuclear cells (chapter 5);
• On a genome-wide level, umbilical cord vein endothelial cells and placental tissue displayed large tissue-specific differences in comparison to umbilical cord white blood cells (chapter 6);
• Extensive genome-wide umbilical cord blood- and placental DNA methylation differences were observed in EOPE, in comparison to preterm birth pregnancies without PE. No significant differential methylation was observed in LOPE pregnancies (chapter 7);
• PE was associated with hypomethylation of the PlGF gene and a lower placental SAM:SAH ratio, more pronounced in EOPE than LOPE (chapter 8).

In conclusion, this thesis provides evidence for associations between prenatal exposure to particularly EOPE and a disturbed development and epigenetic programming of placental and newborn cardiovascular tissues, as potentially underlying mechanism for the association with future cardiovascular risk in offspring.