The role of maternal nutrition and hormones in the regulation of placental nutrient transport and fetal growth

Abstract

Maternal nutrition during pregnancy is an important determinant of fetal growth. Undernutritionmay cause intrauterine growth restriction (IUGR), whereas increased nutrient availability, such asseen in obese women, often result in fetal overgrowth. Both IUGR and fetal overgrowth increasethe risk for perinatal complications and predispose the individual for the development of obesity,diabetes and cardiovascular disease in adult age. Placental nutrient transporters are specificallyaltered in cases of IUGR and fetal overgrowth, changes that are likely to contribute to the alteredfetal growth. However, the mechanisms linking altered maternal nutrient availability to abnormalfetal growth are largely unknown. In these studies we tested the overall hypothesis that maternalmetabolic hormones link maternal nutrition to fetal growth by regulation of key placental nutrienttransporters. We studied (1) maternal nutrient and hormone levels, placental transport functionsand fetal growth in pregnant rats fed control or a low protein (LP) diet, (2) the effect of metabolichormones on amino acid uptake primary human villous fragments and (3) maternal dietary intakeand hormone levels, placental transport functions and fetal growth in a prospective cohort ofpregnant women with early pregnancy BMI ranging from 17-44. In response to a LP dietcirculating levels of insulin, leptin and IGF-I were lowered and the placental capacity to transportamino acids to the fetus was decreased at gestational day (GD) 19. In contrast, there was nosignificant difference in fetal and placental weights between the two groups until GD 21 whenIUGR was observed. These data suggests that the decreased placental capacity to transport aminoacids to the fetus directly contributes to IUGR and that maternal hormones may be involved inthis regulation. In primary villous fragments, leptin and insulin increased the activity of the keyamino acid transporter system A by 37% and 56%, respectively, compatible with the hypothesisthat these hormones contribute to altered fetal growth by regulating placental amino acidtransport. Dietary interviews and maternal blood samples were obtained in 1st and 3rd trimester in49 women with varying BMI, and the placenta was collected in 19 of these women. Maternalenergy intake in both 1st and 3rd trimester were highly correlated to early pregnancy BMI and birthweight. High intake of protein and polyunsaturated fat in 1st trimester and high monounsaturatedfat and carbohydrate intake in 3rd trimester as well as high insulin and leptin levels in 1st and 3rdtrimester and low adiponcetin and IGFBP-I levels in 3rd trimester were all predictors of high birthweight. Protein expression of placental SNAT2, an isoform of system A, was significantlycorrelated with birth weight and maternal insulin levels. We propose a model where key maternalmetabolic hormones constitute a critical link between maternal nutritional status and dietaryintake, and fetal growth mediated by the regulation of placental nutrient transporters. Thesestudies have contributed to advance our understanding of the mechanisms underlyingpathological fetal growth and will provide a foundation for the development of novelintervention and treatment strategies in these conditions.