Maternal and fetal outcomes of pregnancies complicated by obesity

Abstract

There is an increasing prevalence of maternal obesity in Western society. Maternal obesity is associated with adverse maternal and fetal outcomes. Yet, our knowledge of the impact of pre-pregnancy obesity on the hemodynamic adaptations of the mother during pregnancy and postpartum is negligible. The fetal kidney is considered highly sensitive to an adverse intrauterine environment. Surprisingly, the impact of maternal obesity on fetal kidney development is poorly understood. In this thesis, I established a mouse (C57BL6/J) model of diet-induced obesity and used radiotelemetry, cardiac cine-MRI, and urine samples to characterize cardiovascular and renal health. Obese mice demonstrated the major characteristics of human obesity pre-pregnancy including 47% greater body weight, impaired glucose metabolism, hypertension, cardiac hypertrophy, elevated cardiac output and albuminuria. Whilst mean arterial pressure (MAP) and heart rate (HR) remained elevated over control mice throughout pregnancy, the increases in MAP and HR of obese mice during late pregnancy were blunted. Obese dams also failed to increase cardiac output, and left ventricular mass by late pregnancy and albuminuria was exacerbated. These changes in obese dams were associated with greater fetal loss, fetal growth restriction, altered renal morphology and, in male fetuses, a nephron deficit (25%). To determine the effect of pregnancy on the long-term cardiovascular and renal health of obese mice, primiparous obese and control mice were examined 4-weeks post-weaning and compared to time-matched nulliparous mice. Pregnancy led to greater visceral obesity and exacerbated hypertension (light-phase) in obese mice postpartum. Total renal and glomerular collagen content was greater in obese primiparous mice post-partum but this was not related to renal dysfunction with GFR and albuminuria of obese mice unaffected by pregnancy. Maternal obesity in mice has been shown to lead to a nephron deficit in male fetuses (Chapter 3). The ability to assess the contribution of a low nephron endowment to long-term cardiovascular and renal health is often confounded by developmental programming of other organs/systems in many models of nephron deficiency. Thus the choice of model is important so that these confounding factors can be minimized. Interestingly, whilst a low nephron endowment is associated with adult cardiovascular and renal disease, many models of reduced nephron endowment demonstrate normal renal function and MAP. There is little understanding of how renal function is maintained in states of nephron deficit, though nitric oxide (NO) has been implicated. To investigate this, I used a genetic model of reduced nephron endowment the GDNF heterozygous (HET) mouse. This model demonstrates two levels of nephron deficit. Renal function and MAP of GDNF HET mice were examined before and after a 7-day systemic NOS inhibition (L-NAME). Nephron-deficient GDNF HET mice with both moderate and marked nephron deficit were able to maintain normal GFR and sodium balance in response to L-NAME. Further GDNF HET mice demonstrated a partial escape from L-NAME-induced hypertension. These findings indicate that nephron deficient GDNF mice do not rely heavily on NO to maintain renal function chronically. In conclusion, findings of this thesis indicate that pre-pregnancy obesity not only compromises the hemodynamic adaptations of pregnancy leading to poor fetal outcomes but also has a long-term impact on the cardiovascular and renal health of the mother post-partum. Early detection of the risk involved and the development of interventions that enhance pregnancy-initiated hemodynamic adaptations may reduce the long-term impact of pre-pregnancy obesity on the mother and offspring.