Many studies have provided evidence for the hypothesis that size at birth is related to the risk of developing disease in later life. In particular, links are well established between reduced birthweight and increased risk of coronary heart disease, diabetes, hypertension and stroke in adulthood. These relationships are modified by patterns of postnatal growth. The most widely accepted mechanisms thought to underlie these relationships are those of fetal programming by nutritional stimuli or excess fetal glucocorticoid exposure. It is suggested that the fetus makes physiological adaptations in response to changes in its environment to prepare itself for postnatal life. These changes may include epigenetic modification of gene expression. Less clear at this time are the relevance of fetal programming phenomena to twins and preterm babies, and whether any of these effects can be reversed after birth. Much current active research in this field will be of direct relevance to future obstetric practice.

To date, there is no known prenatal treatment for intrauterine growth restriction (IUGR). IGF-I is an important regulator of fetal growth and circulating IGF-I concentrations are reduced in IUGR fetuses. We investigated whether any of three different methods of fetal IGF-I administration would reverse IUGR in sheep. Animals were randomized into five groups: control (n = 17), IUGR + saline (SAL, n = 17), IUGR + iv IGF-I (IGF-IV, n = 14), IUGR + intraamniotic IGF-I (IGF-AF, n = 14), or IUGR + intraamniotic IGF-I with nutrients (IGF-NUT, n = 16). Weekly IGF-I dose was 360 microg in each treatment group. IUGR was induced by placental embolization between 93 and 99 d and treatment was from 100-128 d gestation (term = 147 d). Embolization caused asymmetrical IUGR with reduced fetal growth rates and body and organ weights, but increased brain to liver weight ratio, at post mortem. Embolized fetuses were also hypoxemic and hypoglycemic and had reduced circulating IGF-I and insulin concentrations. IGF-AF and IGF-IV significantly increased fetal growth rates, but only IGF-AF significantly increased fetal liver weight, compared with saline-treated fetuses. Fetal weights and brain to liver weight ratios in all IGF-I-treated fetuses were intermediate between the control and SAL groups. Addition of nutrients reduced the effects of amniotic IGF-I treatment and increased fetal hemoglobin and lactate concentrations. Treatments did not change fetal plasma IGF-I and insulin concentrations. This is the first report of an intrauterine treatment significantly increasing fetal growth rate in established IUGR. Amniotic IGF-I administration may provide the basis for a clinically applicable prenatal treatment for the IUGR fetus.

Protein metabolism may be perturbed in intrauterine growth restriction (IUGR). Arginine is indispensable for growth and nitrogen balance in young mammals. Fetuses with IUGR therefore may benefit from arginine supplementation. The purpose of this study was to determine 1) the effects of IUGR on protein metabolism in the ovine fetus and 2) the effects of arginine or mixed amino acid (AA) infusion on protein metabolism in these fetuses. Pregnant ewes and their fetuses were catheterized at 110 d gestation and randomly assigned to control or IUGR groups. IUGR was induced by repetitive placental embolization. Parameters of fetal protein metabolism were determined from [ring-2 H 5 ]phenylalanine kinetics at baseline and in response to a 4-h infusion of either arginine or an isonitrogenous AA mixture. There were no differences in protein metabolism between control and IUGR groups either at baseline or in response to arginine or AA treatment. Both arginine and AA infusion increased fetal protein accretion in both groups. Arginine did this by decreasing protein turnover, synthesis, and breakdown. AAs increased protein turnover and synthesis while decreasing protein breakdown. AA infusion resulted in a significantly higher increase in protein accretion than arginine infusion. Thus, in the ovine fetus, placental embolization has no clear effect on protein metabolism. Arginine and AAs both stimulate protein accretion but do so in distinctly different ways. Mixed AA infusion has a greater effect on protein accretion than arginine alone and therefore may be a better strategy for stimulating fetal growth. Intrauterine growth restriction (IUGR) is a major cause of perinatal mortality and morbidity (1,2). Although there are many possible causes, the key feature of IUGR is impaired fetal growth and, hence, by inference, impaired protein accretion. However, there are few data describing the alterations in protein metabolism that must underlie IUGR.In the IUGR human neonate, the few studies available are conflicting (3-5). Protein accretion rates are reported to be normal, although both increased (3,4) and reduced (5) protein synthesis and turnover have been reported. A previous study on protein kinetics in the ovine fetus in which growth was restricted by heat stress showed no significant changes in protein synthesis, breakdown, or accretion (6). However, a number of reports provide indirect evidence of altered protein metabolism in human fetuses with IUGR. In human pregnancies that are complicated with IUGR, fetal plasma AA concentrations are reduced (7,8), and this persists after birth (9). Concentrations of most essential AAs are lower, particularly those of the branched-chain AAs valine, isoleucine, and leucine (7,9). The maternal plasma AA concentrations are higher than in uncomplicated pregnancies and often not significantly different from nonpregnant controls (8).There is also indirect evidence of impaired urea production in association with IUGR. Plasma and urinary urea levels are

Frequent treatment of the growth-restricted (IUGR) ovine fetus with intra-amniotic IGF-1 increases fetal growth. We aimed to determine whether increased growth was maintained with an extended dosing interval and to examine possible mechanisms. Pregnant ewes were allocated to three groups: Control, and two IUGR groups (induced by placental embolization) treated with weekly intra-amniotic injections of either saline (IUGR) or 360 µg IGF-1 (IGF1). IUGR fetuses were hypoxic, hyperuremic, hypoglycemic, and grew more slowly than controls. Placental glucose uptake and SLC2A1 (GLUT2) mRNA levels decreased in IUGR fetuses, but SLC2A3 (GLUT3) and SLC2A4 (GLUT4) levels were unaffected. IGF-1 treatment increased fetal growth rate, did not alter uterine blood flow or placental glucose uptake, and increased placental SLC2A1 and SLC2A4 (but not SLC2A3) mRNA levels compared with saline-treated IUGR animals. Following IGF-1 treatment, placental mRNA levels of isoforms of the system A, y+, and L amino acid transporters increased 1.3 to 5.0 fold, while the ratio of phosphorylated-mTOR to total mTOR also tended to increase. Weekly intra-amniotic IGF-1 treatment provides a promising avenue for intra-uterine treatment of IUGR babies, and may act via increased fetal substrate supply, up-regulating placental transporters for neutral, cationic, and branched-chain amino acids, possibly via increased activation of the mTOR pathway.