Birth weight, infant growth and insulin resistance.

Size at birth and early postnatal growth rates are important determinants of human perinatal survival; they also predict the tempo of growth, adult height and long-term risks for obesity, type 2 diabetes and cardiovascular disease. Results from the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC) show that fetal growth is influenced by both fetal genes and maternal-uterine-placental factors. Important maternal-placental factors include parity, smoking and weight gain, but also maternal genetic factors in the mother or fetal placenta, including the mitochondrial DNA 16189 variant and H19. These maternal genetic factors particularly influence smaller, growth-restrained infants, as in first pregnancies. Fetal genes include the insulin gene (INS) VNTR (variable number of tandem repeat), which we recently confirmed to be associated with birth size and cord blood IGF-II levels; these fetal gene effects are more evident in the absence of maternal-uterine growth restraint. During postnatal life, the INS VNTR III/III genotype remains associated with body size, including body mass index and waist circumference, and also lower insulin sensitivity among girls. However, as at birth, significant gene-environment interactions are seen. Rapid 'catch-up' early postnatal weight gain follows maternal-uterine restraint, and strongly predicts later childhood obesity and insulin resistance; among these children, those with INS VNTR class I alleles are more obese. Genetic factors that influence early growth may have conferred some early survival advantage in human history during times of undernutrition. With abundant nutrition and rising obesity rates, these genetic factors and their interactions with maternal and childhood environmental factors that influence childhood growth may now contribute to the early development of adult disease risk. Their recognition may help the development of targeted early interventions to prevent the progression towards adult disease.