| Summary: | <p>It is becoming increasingly clear that exposure to pregnancy complications such as hypertensive disorders of pregnancy and premature birth (birth before 37 weeks gestation) have a long term and specific effect on future cardiovascular disease development and risk in the offspring. Those born to a preeclamptic pregnancy have been shown to have double the risk of stroke in adulthood and studies have consistently shown an increase in blood pressure in these individuals. Higher blood pressure has also been observed in those born preterm in addition to specific cardiac modifications in young adulthood.</p> <p>Through detailed cardiovascular phenotyping, this thesis investigates the effects of exposure to <em>in utero</em> maternal hypertension and/or a preterm birth on offspring cardiovascular development in the antenatal and early postnatal period in a newly established cohort of infants. A stratified recruitment strategy was employed in order to recruit similar numbers of mother and infant dyads from hypertensive and normotensive pregnancies across a range of gestations.</p> <p>Nomograms for fetal ventricular volume and mass using two dimensional echocardiography were created. These were then used, along with postnatal normative data, to create trajectories of offspring cardiovascular development from 15 weeks postmenstrual age through to three months post birth in order to overlay datasets from babies born preterm. It was demonstrated that premature infants have similar in utero cardiac development to controls but post birth they undergo disproportionate cardiac hypertrophy which is associated with a degree of diastolic impairment. Preterm infants at birth had a unique ventricular shape, but these changes had attenuated by three months of age. Exposure to <em>in utero</em> maternal hypertension also appeared to have a deleterious effect and on further investigation, postnatal ventricular hypertrophy was also observed when analysis was restricted to term born infants exposed to this pregnancy complication.</p> <p>Additionally, offspring born to a hypertensive pregnancy demonstrated an increased microvascular density loss over the first three months of life. This was associated with a reduction in vasculogenic potential in their human umbilical vein endothelial cells and also increased levels of maternal anti-angiogenic biomarkers at birth. Again, there was a trend to suggest maternal hypertension and prematurity may have an additive effect. These microvascular changes were not, however, correlated with cardiac hypertrophy in the whole cohort over the same period, but, intriguingly, when subgroup analysis was performed, increased microvascular density loss was correlated with increased left ventricular mass indexed to body size at three months of age in term born infants but not in the preterm group.</p> <p>It was then shown that preterm offspring had reduced heart rate variability measures at birth suggesting autonomic dysfunction. This was, however, not correlated with any previously demonstrated cardiovascular developmental changes in the early postnatal period. Offspring exposed to maternal hypertension and those born small for gestational age did not demonstrate any difference in heart rate variability at birth compared to controls.</p> <p>The results from my thesis point towards the perinatal and early postnatal period as being a critical window for cardiovascular development. As up to 8% of pregnancies are affected by hypertensive disorders of pregnancy and approximately 10% of all births are preterm, understanding the mechanisms behind these findings and their relevance to long term cardiovascular disease in this population is of great public health interest. Modification of clinical care and discovery of novel targets for disease prevention during this potentially tractable period will be of future interest.</p>
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