Long-Term Outcomes After Intrauterine Therapy of the Growth-Restricted Fetus

The experiments described in this thesis investigated the effects of intra-amniotic insulin-like growth factor-1 (IGF1) treatment of fetal growth restriction (FGR) in the ovine fetus on perinatal morbidity and mortality, on growth from birth through 18 months of age, and on metabolic and endocrine function at 18 months of age. Ewes carrying singleton lambs (n=196) were randomised to un-operated Controls (n=41) or to FGR (n=144), induced by uteroplacental embolisation. FGR fetuses were further randomised to receive either 360 μg recombinant human IGF1 (FGR-IGF1, n=61) or saline (FGR-Saline, n=66) intra-amniotically once weekly for 5 weeks. IGF1 treatment of FGR did not affect fetal or perinatal morbidity or mortality. FGR-Saline lambs (n=31) were 15-20% lighter at birth than Controls (n=37). Growth velocity for weight in the first week after birth was 18% greater (p<0.05) in FGR-Saline lambs compared with Controls, but in the second week was 15% greater (p<0.01) in FGR-IGF1 lambs (n=32) compared with Controls. FGR-IGF1 females had ~10% increase in relative lean mass and ~10% decrease in relative visceral adipose (both, p<0.05) compared with Controls at 18 months of age. One week after birth, FGR-IGF1 females had greater GHR and IGF1 mRNA expression than FGR-Saline (p<0.01), and FGR-IGF1 males had greater IGF1 mRNA expression (p<0.01), in skeletal muscle. Up-regulated skeletal muscle IGF1 mRNA expression persisted in FGR-IGF1 males and females at 18 months of age following growth hormone stimulation compared with Control and FGR-Saline offspring (p<0.01). In FGR-Saline adult females, insulin sensitivity (Si) and glucose disposition (DIG) tended to be decreased by ~50% and ~24% respectively compared with Controls. These changes were reversed in FGR-IGF1 females. Plasma insulin secretion in the first 15 minutes of a glucose tolerance test and DIG were ~80% greater in FGR-IGF1 females compared to FGR-Saline. In FGR-IGF1 males the maximal change ii in ˪-Arginine-stimulated insulin secretion was increased by 40% and Si tended to be greater (by ~67%) than FGR-Saline. FGR-IGF1 adult males had a 34% greater increase in plasma ACTH concentration (p<0.05) in response to corticotrophic stimulation compared to FGR-Saline males. In contrast, in response to Metyrapone FGR-IGF1 females’ peak ACTH response and 11-deoxycortisol area under the curve tended to be decreased (20% and ~40%, respectively), compared with Controls. These data demonstrate that, although intra-amniotic IGF1 treatment of the FGR fetus did not alter fetal or perinatal mortality, it prolonged the accelerated growth velocity for weight in the perinatal period and was associated with decreased relative visceral adipose and increased relative lean mass in adult females. Sex-specific effects on HPA axis function could have implications for wellbeing as age progresses. There were few other significant effects on adult endocrine or metabolic function indicating that IGF1 treatment of FGR is not associated with significant adverse effects through young adulthood, but does not provide dramatic benefits, suggesting that this is unlikely to be utilised as a clinical intervention.