Placental restriction and endocrine control of postnatal growth

Abstract

Intrauterine Growth Restriction (IUGR) is evident in infants born with a reduced weight or length, and/or increased thinness for gestational age. IUGR is associated with altered postnatal growth and regulation, due to unknown mechanisms. Much clinical IUGR results from the reduced delivery of essential substrates (oxygen and nutrients) to the fetus, due to either maternal or placental limitations. Catch-up growth (accelerated rate of growth in absolute or fractional terms) occurs in the majority of IUGR infants, and returns an infant to their predetermined growth curve. IUGR is associated with increased risks of morbidity and mortality in the perinatal period, and with a reduced final adult stature and increased risk of adult onset diseases, particularly diabetes and cardiovascular disease. Catch-up growth after IUGR predicts improved health in terms of reduced hospital visits in infants and children, and an increased final adult stature but also predicts an increased risk of developing obesity, as well as diabetes and cardiovascular disease. The underlying mechanisms for catch-up growth may contribute to this range of outcomes in later life, but are poorly understood. Studies in IUGR infants have demonstrated increased absolute and/or fractional growth rates following birth, termed catch-up growth, in the presence of reduced or normal plasma concentrations of the thyroid hormones and major anabolic hormones (insulin and/or IGF-I). This suggests that increased sensitivity to, rather than increased production of insulin, IGF-I and thyroid hormone, causes catch-up growth following IUGR. We therefore hypothesised that placental restriction of fetal growth would reduce size at birth and increase postnatal growth and adiposity in association with increased metabolic sensitivity to insulin, IGFs and thyroid hormones. This study has shown that the placentally restricted (PR) lamb has a reduced size at birth in terms of soft and skeletal tissues, has increased rates of growth postnatally, and has increased adiposity by six weeks of age. We have also shown that PR of fetal growth in the sheep did not alter gestational age at delivery, but reduced survival rate. PR lambs demonstrated catch-up growth in most parameters by 30 days of age and increased adiposity at six weeks of age compared to the control lambs. Placental restriction increased insulin and IGF sensitivity of circulating free fatty acids, which in turn, predicts increased adiposity. Neonatal catch-up growth after fetal growth restriction was substantially predicted by both abundance of, and metabolic sensitivity to insulin, suggesting increased insulin action as an underlying cause. Catch-up growth occurs in the neonate despite reduced concentrations of fasting plasma IGFs, along with increased IGF sensitivity of free fatty acid metabolism and adiposity. Plasma TH concentrations predicted growth of soft and skeletal tissue in lambs during early postnatal life, particularly in those undergoing catch-up growth following PR. Therefore neonatal catch-up growth after IUGR is associated with increased sensitivity to both insulin and IGFs, particularly of circulating free fatty acids, and appears to occur to the extent allowed by the prevailing abundance of these hormones and of thyroid hormones. If this altered endocrine state persists, increased adiposity and its subsequent amplification may contribute to the development of obesity, and related adverse metabolic and cardiovascular outcomes in adult life.