The Long Term Consequences of Preterm Birth and Neonatal Growth Rates in Lambs

Abstract

Preterm birth is associated with adverse health outcomes. However, it is not known whether preterm birth itself causes these outcomes, or whether they are due to other factors that frequently co-exist including antenatal corticosteroid exposure, nutritional supplementation and altered postnatal growth rates. The experiments described in this thesis investigated the effects of gestation length, antenatal corticosteroid exposure, nutritional supplementation and postnatal growth rates on later cardiovascular and metabolic outcomes in sheep. Ewes with singleton lambs (n=208) were randomised to corticosteroid-induced preterm birth (preterm, n=60), spontaneous term birth (term-spont, n=73), corticosteroid-induced term birth (termdex, n=52), or non-corticosteroid induced term birth (term-Alizin, n=16). Term-spont, termdex and preterm lambs were also randomised to receive nutrient or water supplements from birth to 2 weeks. Pilot studies of in utero growth restriction were also undertaken to investigate the effects of poor fetal growth. Preterm birth in male sheep and reducing gestation length in female term-spont sheep led to increased cardiac sympathetic and reduced parasympathetic activity in adulthood; changes associated with increased cardiovascular risk in humans. Antenatal corticosteroid exposure had no effect on cardiovascular or metabolic outcomes. Nutritional supplementation had different sex-specific effects following preterm and term birth. In term-spont males, supplementation decreased weight gain and weight-for-length between 2 weeks of age and weaning and reduced adult fat mass by  40% (not statistically significant). Conversely, in preterm males supplementation increased weight-for-length between 2 weeks and weaning without affecting adult fat mass. In term-spont females, supplementation reduced dextroseand arginine-stimulated insulin secretion by 50-60% at 18 weeks, whereas in preterm females, supplementation increased arginine-stimulated but not dextrose stimulated insulin secretion by  50%. These effects of preterm birth and nutritional supplementation were not mediated by variations in postnatal growth rate. These findings demonstrate that in sheep, reduced gestation length alters cardiac autonomic function and that a brief nutritional intervention has consequences for growth and pancreatic function into adulthood. Research in humans is needed to investigate whether the cardiovascular risk following preterm birth is mediated by altered autonomic function, and to assess the long-term metabolic consequences of nutritional strategies aimed at increasing neonatal growth rates.