This thesis examines changes in the maternal vascular response both within and remote from pregnancy. Prior studies investigating the association between pregnancy, breastfeeding and maternal cardiovascular dysfunction have reported conflicting results, and much remains to be elucidated regarding the physiological mechanisms of vasodilatation and vasoconstriction during pregnancy and in the postpartum period. It is known that maternal mechanisms of vasodilatation become disturbed in hypertensive disorders of pregnancy (HDP); therefore, understanding the physiological alterations to the maternal cardiovascular system which occur in healthy, normotensive pregnancy and how these adaptations are disturbed in hypertensive disorders is crucial to elucidating the pathogenesis of HDP. It has not previously been possible to study these changes, due to the relative inaccessibility of the microcirculation. The development of retinal imaging, a new method of visualising the peripheral vasculature in vivo, now makes this investigation possible. This thesis details two studies investigating the maternal vascular responses within and remote from pregnancy. The first study, presented in Chapter 2, investigates the effect of pregnancy on remote maternal cardiovascular health through an analysis of the association between parity and breastfeeding with remote maternal hypertension. Baseline data for 74,785 women were sourced from the 45 and Up Study, Australia, a cross-sectional cohort study. The women included wereaged45 years or older, had an intact uterus, and had not been diagnosed with high blood pressure before pregnancy. Odds ratios (ORs) and 99% confidence intervals (CIs) for the association between giving birth, breastfeeding, lifetime breastfeeding duration, and average breastfeeding per child with high blood pressure were estimated using logistic regression. The combination of parity and breastfeeding was associated with lower odds of having high blood pressure (adjusted OR: 0.89, 99% CI: 0.82-0.97, P< 0.001), compared with nulliparous women, whereas there was no significant difference between mothers who did not breastfeed and nulliparous women (adjusted OR: 1.06, 99% CI: 0.95-1.18, P = 0.20). Women who had breastfed for longer than six months in their lifetime, or for longer than an average of three months per child, had significantly lower odds of having high blood pressure when compared with parous women who had never breastfed. The odds were further lowered with longer breastfeeding durations. These results are discussed with reference to repeated exposure to oxytocin throughout the breastfeeding period. The second study detailed in this thesis investigated the changes which occur to the maternal microvasculature within pregnancy. This study is presented in Chapters 3, 4 and 5. Initially, changes to the maternal retinal microvasculature and blood pressure during healthy pregnancy are reported, using the results from a prospective cohort study. In this study, fifty three women were recruited from Royal Prince Alfred Hospital (RPAH) in Sydney, a large tertiary hospital. Retinal images and blood pressure readings were collected at four time points during pregnancy (13, 19, 29 and 38 weeks gestation) and at six weeks postpartum. Retinal images were analysed for the central retinal arteriolar equivalent (CRAE) and the central retinal venular equivalent (CRVE). Mean arterial blood pressure (MAP) was calculated from blood pressure readings. There was a decrease in MAP between 13 and 19 weeks gestation (79.0 ± 1.3 mm Hg to 74.6 ± 1.4 mm Hg, P = 0.001) followed by a return to baseline from 19 weeks to delivery. This was correlated with an increase in vessel caliber between 13 and 19 weeks gestation (CRAE: 167.0 ± 2.3 Im and 173.6 ± 2.1 Im, P < 0.001; CRVE: 231.2 ± 3.1 Im and 238.1 ± 3.0 Im, P = 0.007) and a return to baseline from 19 weeks to delivery. There were no differences in the CRAE or CRVE (both uncorrected and corrected for MAP) between nulliparous and parous women. The pattern of dilatation and constriction in the microvasculature mirrored the changes in MAP throughout pregnancy, reflecting changes in peripheral resistance. The temporal changes to retinal vascular calibre throughout hypertensive pregnancy (grouped into gestational hypertension and preeclampsia) are then studied and compared with findings from normotensive pregnancy. A novel method is established quantifying maternal peripheral vascular resistance. This method is the correction of retinal vascular calibre by the mean arterial blood pressure, forming the corrected central retinal arteriolar equivalent (cCRAE) and the corrected central retinal venular equivalent (cCRVE). This method enables an in vivo analysis of changes to peripheral vascular resistance in both healthy and hypertensive pregnancy, and allows comparison to be made of peripheral vascular resistance within a group of women or in individual women over time. In this study, 100 women were recruited from RPAH, of which 83 had a normotensive pregnancy, eight developed gestational hypertension and nine developed preeclampsia. Retinal images and blood pressures were collected at 13, 19, 29, and 38 weeks of gestation. Retinal vessels and blood pressure were analyzed as the cCRAE and the CRVE, using generalized linear models adjusted for age and body mass index. There was a significant difference in the cCRAE between the normotensive and gestational hypertension groups at the 13 week (P = 0.02) and 38 week (P = 0.03) time points. In comparing the normotensive and preeclampsia groups, it was observed that the cCRAE was significantly reduced at 13 (P = 0.03), 19 (P = 0.007) and 38 (P = 0.03) weeks gestation in the preeclampsia group. The cCRVE was also significantly lower at 13 (P = 0.04) and19 (P = 0.001) weeks of gestation in the women who progressed to preeclampsia when compared to the normotensive group. The observed disturbances in vasodilatory mechanisms in women who progress to HDP are then discussed. Body mass index (BMI), a recognised risk factor for vascular disease, was then correlated with changes to the maternal microvasculature throughout healthy pregnancy. This study included 79 women recruited from RPAH. Of these women, 60 had a BMI in the healthy range (BMI 18.5 to < 25.0 kg/m2), 13 had a BMI in the overweight range (BMI 25.0 to < 30.0 kg/m2) and six women had a BMI in the obese range (BMI ≥ 30.0 kg/m2). Retinal images and blood pressures were collected at 13, 19, 29 and 38 weeks gestation. Blood pressure readings were used to calculate MAP. An analysis of the cCRAE revealed that there were no significant differences between healthy weight and overweight participants at any time point. A comparison of the healthy weight and obese groups showed a significantly reduced cCRAE in the obese group at 19 weeks (P = 0.006) and 38 (P = 0.02) weeks gestation. Analysis of the cCRVE revealed a reduction at 38 weeks gestation between the healthy weight and overweight participants (P=0.002). Between the healthy weight and obese weight participants a reduced cCRVE was observed in the obese group at 38 weeks gestation when compared to the healthy weight group (P< 0.001). Maternal vascular changes within pregnancy are then studied through an analysis of angiogenic biomarkers in pregnancies complicated by HDP in comparison with normotensive pregnancies (presented in Chapter 6). Plasma from 30 women (20 who had a normotensive pregnancy, 10 who developed a hypertensive disorder of pregnancy) was collected at 13 weeks gestation. Samples were analysed using enzyme-linked immunosorbent assays to determine levels of vascular endothelial growth factor (VEGF), soluble fms-related tyrosine kinase-1, placental growth factor and soluble endoglin. A significant difference in the VEGF concentration was observed between the HDP and the control group (P = 0.04), with significantly higher levels of VEGF observed in the HDP group. These findings are then discussed in reference to endothelial dysfunction. Finally, an analysis is made in Chapter 7 of the combined findings in this thesis. Endothelial dysfunction is discussed as a mediator of pathologic maternal vascular changes within and remote from pregnancy.
| Date of Award | 2013 |
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| Original language | English |
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