The Influence of Micronutrients on Placental Development and Pregnancy Outcome

Appropriate placental development and function is intricately associated with pregnancy success. Indeed, placental function is essential for adequate fetal development in utero, as well as orchestrating maternal physiological adaptations to pregnancy. However, the incidence of pregnancy complications that are characterised by placental dysfunction is increasing. Whilst a significant amount is understood about the down-stream effects of placental dysfunction, the causes are poorly understood. Inadequate maternal micronutrient status has been identified as a risk factor for adverse pregnancy outcome; even small perturbations in micronutrient homeostasis can have significant consequences for cellular and physiological pathways. The overall goal of this research was to further the understanding of how maternal micronutrient status during pregnancy influences placental development and pregnancy outcome with a focus on trace elements: zinc, copper and selenium, as well as calcium and vitamin D. Initially, a systematic review of the literature identified possible associations between maternal zinc deficiency and hypertensive disorders of pregnancy, as well as the delivery of small-for-gestational age or low birthweight infants. Based on these results, an in-depth analysis of the effects of zinc deficiency on placental morphogenesis and maternal haemodynamic changes during pregnancy was conducted in a mouse model. This study confirmed maternal zinc status to be a key determinant of fetal growth, the effects of limited zinc on fetal growth restriction were likely to be mediated through adverse placental development and that altered placental function was associated with improper maternal cardiovascular adaptations to pregnancy. Next, a large-scale human epidemiological study was undertaken focusing on maternal trace elements, calcium and vitamin D status and risk of pregnancy complications in the SCreening fOr Pregnancy Endpoints (SCOPE) study. Of particular interest, this research showed a clear association between plasma copper in early pregnancy and the risk of developing any pregnancy complication with the data suggesting a possible mechanistic role for elevated free copper and inflammatory responses within the placenta. Furthermore, markers of calcium status were associated with inappropriate placental function and reduced fetal growth. This highlighted the importance of calcium in pregnancy and offered a hypothesis for the disparate published findings on the association between vitamin D deficiency and adverse pregnancy outcomes. Finally, one possible mechanism by which micronutrient deficiencies may impact placental morphogenesis is through altered epigenetic programming. Optimisation of visualisation techniques: immunohistochemistry and immunofluorescence, to study DNA methylation in different cell types offers a unique avenue in which to study how micronutrients influence the epigenome. The research presented confirmed that DNA methylation markers differed between different placenta cell types and that these patterns of localization are dynamic across gestation. These changes are likely to impact placental function and offer some insight into possible changes found in the epigenome in pregnancies complicated by placental dysfunction. In summary, this PhD research offers a unique perspective on the importance of adequate nutrition during pregnancy and a platform for future endeavours seeking to understand how micronutrients support placental development and pregnancy outcome.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 201