Clinical review 68: The endocrine regulation of fetal growth in late gestation: the role of insulin-like growth factors.

Abstract

I NTRAUTERINE growth retardation (IUGR) remains a dominant cause of perinatal morbidity and mortality. More recently, it has been suggested that IUGR has longerterm effects on morbidity and mortality. A causal association between IUGR and the subsequent development of maturityonset diabetes mellitus and cardiovascular disease in adulthood has been suggested; one postulated mechanism to explain this association is that IUGR may lead to altered programming of endocrine development (1). The causes of IUGR can be considered in three major groupings. It may be secondary to the effects of toxins affecting fetal or placental cell division (e.g. fetal infection), to genetic abnormalities (e.g. trisomy 21), or to disturbance of the supply of nutrients from mother to fetus (e.g. maternal cardiovascular disease, placental pathology, hypertension of pregnancy, and maternal undernutrition). The latter group represents the group in which the greatest potential for clinical intervention may lie. Strategies aimed at coordinately enhancing placental function are the only potential therapeutic approaches to in utero therapy at a gestational age before safe premature delivery by cesarean section. However, such strategies remain theoretical, as little is known of the factors that might regulate nutrient transfer across the placenta. It is well established that the maternal phenotype is a major determinant of fetal growth in late gestation. Under most circumstances, the limited capacity of the placenta to transfer nutrients to the fetus constrains the growth of the fetus; for example, transfer of an embryo of a small breed into the uterus of a larger breed will overcome this constraint and lead to a larger birth size than observed within the homologous breed (2). This phenomenon of maternal constraint is reflected in the smaller average birth size of multiple pregnancies. It is assumed to reflect several mechanisms, including limitations on uterine blood flow and the limited capacity of placental transfer mechanisms. Thus, the endocrine regulation of fetal growth in late gestation is determined by hormones that influence the parti-