Intermittent maternofetal oxygenation during late gestation improved birthweight, neonatal growth, body symmetry, and muscle metabolism in intrauterine growth-restricted lambs

Abstract

Abstract In humans and animals, intrauterine growth restriction (IUGR) results from fetal programming responses to poor intrauterine conditions. Chronic fetal hypoxemia elevates circulating catecholamines, which reduces skeletal muscle β2 adrenoceptor content and contributes to growth and metabolic pathologies in IUGR-born offspring. Our objective was to determine whether intermittent maternofetal oxygenation during late gestation would improve neonatal growth and glucose metabolism in IUGR-born lambs. Pregnant ewes were housed at 40 °C from the 40th to 95th day of gestational age (dGA) to produce IUGR-born lambs (n = 9). A second group of IUGR-born lambs received prenatal O2 supplementation via maternal O2 insufflation (100% humidified O2, 10 L/min) for 8 h/d from dGA 130 to parturition (IUGR+O2, n = 10). Control lambs (n = 15) were from pair-fed thermoneutral ewes. All lambs were weaned at birth, hand-reared, and fitted with hindlimb catheters at day 25. Glucose-stimulated insulin secretion (GSIS) and hindlimb hyperinsulinemic-euglycemic clamp (HEC) studies were performed at days 28 and 29, respectively. At day 30, lambs were euthanized and ex vivo HEC studies were performed on isolated muscle. Without maternofetal oxygenation, IUGR lambs were 40% lighter (P < 0.05) at birth and maintained slower (P < 0.05) growth rates throughout the neonatal period compared with controls. At 30 d of age, IUGR lambs had lighter (P < 0.05) hindlimbs and flexor digitorum superficialis (FDS) muscles. IUGR+O2 lambs exhibited improved (P < 0.05) birthweight, neonatal growth, hindlimb mass, and FDS mass compared with IUGR lambs. Hindlimb insulin-stimulated glucose utilization and oxidation rates were reduced (P < 0.05) in IUGR but not IUGR+O2 lambs. Ex vivo glucose oxidation rates were less (P < 0.05) in muscle from IUGR but not IUGR+O2 lambs. Surprisingly, β2 adrenoceptor content and insulin responsiveness were reduced (P < 0.05) in muscle from IUGR and IUGR+O2 lambs compared with controls. In addition, GSIS was reduced (P < 0.05) in IUGR lambs and only modestly improved (P < 0.05) in IUGR+O2. Insufflation of O2 also increased (P < 0.05) acidosis and hypercapnia in dams, perhaps due to the use of 100% O2 rather than a gas mixture with a lesser O2 percentage. Nevertheless, these findings show that intermittent maternofetal oxygenation during late gestation improved postnatal growth and metabolic outcomes in IUGR lambs without improving muscle β2 adrenoceptor content.