Adult Sequelae of Intrauterine Growth Restriction

Abstract

Fetal intrauterine growth restriction has been associated with adult disease in both human epidemiologic studies and in animal models. In some cases, intrauterine deprivation programs the fetus to develop increased appetite and obesity, hypertension and diabetes as an adult. Although the mechanisms responsible for fetal programming remain poorly understood, both anatomic and functional (cell signaling) changes have been described in affected individuals. In some animal models, aspects of fetal programming can be reversed postnatally, however at the present time the best strategy for avoiding the adult consequences of fetal growth restriction is prevention.Fetal intrauterine growth restriction (IUGR) occurs in humans as a consequence of poor maternal nutrition, placental insufficiency and diminished fetal oxygenation, or exposure to teratogens, among other causes. In animals, and in some cases in humans, IUGR from these causes has been associated with the development of adult diseases; this phenomenon is called "fetal programming". The association of maladaptive programming with adult disease has been termed the "Barker hypothesis". In general, the Barker hypothesis 1 contends that the malnourished fetus is programmed to exhibit a "thrifty phenotype" with increased food intake and fat deposition and possibly decreased energy output. Faced with ample available calories, such individuals develop obesity and other manifestations of the metabolic syndrome as adults due to alterations in homeostatic regulatory mechanisms. 2-4The issue of fetal programming is not merely of intellectual interest. Currently, 65% of adults in the United States are overweight and almost one in three are obese (BMI>30 kg/m 2 ), representing a modern health crisis. 5 Obesity and its related diseases are the leading cause of death in Western society, with associated risks of hypertension, coronary heart disease, stroke, diabetes, and breast, prostate and colon cancer. Evidence indicates a striking 25 to 63% of adult diabetes, hypertension and coronary heart disease can be attributed to the effects of low birthweight with accelerated newborn-to-adolescent weight gain. 2 therefore gestational programming of low birth weight/ IUGR has contributed importantly to the population shift towards obesity. In Western societies, the incidence of low birth weight infants has increased since the mid-twentieth century. Low birth weight infants are now being born to women with chronic diseases who would previously have had limited survival and reproductive capacity, while assisted reproductive technologies and increasing numbers of multiple gestations have resulted in both preterm and low birth weight offspring. When combined with improved

Maternal protein restriction leads to enhanced hepatic gluconeogenic gene expression in adult male rat offspring due to impaired expression of the liver X receptor

“…We present evidence for the first time that suppressed expression of LXRa may mediate the enhanced transcription of the gluconeogenic genes G6pase and 11b-Hsd1 due to its decreased binding on these promoters, ultimately removing its ability to suppress hepatic gluconeogenesis (Stulnig et al 2002a, Cao et al 2003, Laffitte et al 2003, Mitro et al 2007). Given placental insufficiency in humans can produce protein deficiency in the fetus (Crosby 1991), this LP model shares features in common with PI-IUGR (Ross & Beall 2008). Previous studies done in our laboratory with the same cohort of animals have already demonstrated that LP offspring exhibit a 15% lower fetal to placental weight ratio and a 40% decreased fetal liver to body weight ratio at embryonic day 19 (Sohi et al 2011).…”

Development of a New Nordic Diet score and its association with gestational weight gain and fetal growth – a study performed in the Norwegian Mother and Child Cohort Study (MoBa)

“…lead to increased cardiovascular risk later in life (33,34) . The fact that high as compared with low NND adherence also implied an estimated 7 % higher adjusted odds of the infant being born LGA indicates that factors associated with better diet quality may improve fetal substrate availability and enhance fetal growth in general.…”

Is Breastfeeding Protective for Blood Pressure in Schoolchildren? A Cohort Study in Northeast Brazil

“…22 The introduction of formula in the neonatal period for infants with intrauterine growth restriction, as a total or partial replacement for breastfeeding, provides a sodium content three times greater than those receiving exclusive breastfeeding. 23,24 In addition, it may also be observed that lowbirth-weight infants present vascular endothelial dysfunction, and this situation can be aggravated by a short duration of breastfeeding, possibly increasing the biological risks associated with low birth weight.…”