Fetal Programming of Body Composition, Obesity, and Metabolic Function: The Role of Intrauterine Stress and Stress Biology

Epidemiological, clinical, physiological, cellular, and molecular evidence suggests that the origins of obesity and metabolic dysfunction can be traced back to intrauterine life and supports an important role for maternal nutrition prior to and during gestation in fetal programming. The elucidation of underlying mechanisms is an area of interest and intense investigation. In this perspectives paper we propose that in addition to maternal nutrition-related processes it may be important to concurrently consider the potential role of intrauterine stress and stress biology. We frame our arguments in the larger context of an evolutionary-developmental perspective that supports roles for both nutrition and stress as key environmental conditions driving natural selection and developmental plasticity. We suggest that intrauterine stress exposure may interact with the nutritional milieu, and that stress biology may represent an underlying mechanism mediating the effects of diverse intrauterine perturbations, including but not limited to maternal nutritional insults (undernutrition and overnutrition), on brain and peripheral targets of programming of body composition, energy balance homeostasis, and metabolic function. We discuss putative maternal-placental-fetal endocrine and immune/inflammatory candidate mechanisms that may underlie the long-term effects of intrauterine stress. We conclude with a commentary of the implications for future research and clinical practice

Prenatal maternal stress programs infant stress regulation.

Prenatal exposure to inappropriate levels of glucocorticoids (GCs) and maternal stress are putative mechanisms for the fetal programming of later health outcomes. The current investigation examined the influence of prenatal maternal cortisol and maternal psychosocial stress on infant physiological and behavioral responses to stress.The study sample comprised 116 women and their full term infants. Maternal plasma cortisol and report of stress, anxiety and depression were assessed at 15, 19, 25, 31 and 36 + weeks' gestational age. Infant cortisol and behavioral responses to the painful stress of a heel-stick blood draw were evaluated at 24 hours after birth. The association between prenatal maternal measures and infant cortisol and behavioral stress responses was examined using hierarchical linear growth curve modeling.A larger infant cortisol response to the heel-stick procedure was associated with exposure to elevated concentrations of maternal cortisol during the late second and third trimesters. Additionally, a slower rate of behavioral recovery from the painful stress of a heel-stick blood draw was predicted by elevated levels of maternal cortisol early in pregnancy as well as prenatal maternal psychosocial stress throughout gestation. These associations could not be explained by mode of delivery, prenatal medical history, socioeconomic status or child race, sex or birth order.These data suggest that exposure to maternal cortisol and psychosocial stress exerts programming influences on the developing fetus with consequences for infant stress regulation

Sensitization of cardiac responses to pain in preterm infants.

BackgroundPreterm infants are repeatedly exposed to painful experiences as part of their care in the neonatal intensive care unit. There is evidence from both animal and human studies that exposure to pain during the neonatal period may have persisting consequences for development.ObjectiveTo perform serial assessments of three heelstick blood draws to examine early changes both in physiological and behavioral responses to repeated exposure to painful stimuli in preterm infants.MethodsHeart rate and behavioral responses to three serially administered heelstick blood draws were evaluated in 22 medically stable preterm infants with less than 48 h of mechanical ventilation who were admitted to the neonatal intensive care unit.ResultsHeart rate and behavioral agitation significantly increased during each heelstick as compared to baseline. The heart rate response was larger to the third heelstick as compared to the first two procedures. Behavioral responses did not change across the three assessments.ConclusionsHealthy preterm infants sensitize to heelstick-induced pain, as measured by their heart rate responses. These data suggest that greater attention to the effects of repeated pain for the neonate is needed

Prenatal Maternal Stress Programs Infant Stress Regulation

Objective: Prenatal exposure to inappropriate levels of glucocorticoids (GCs) and maternal stress are putative mechanisms for the fetal programming of later health outcomes. The current investigation examined the influence of prenatal maternal cortisol and maternal psychosocial stress on infant physiological and behavioral responses to stress. Methods: The study sample comprised 116 women and their full term infants. Maternal plasma cortisol and report of stress, anxiety and depression were assessed at 15, 19, 25, 31 and 36 + weeks\u27 gestational age. Infant cortisol and behavioral responses to the painful stress of a heel-stick blood draw were evaluated at 24 hours after birth. The association between prenatal maternal measures and infant cortisol and behavioral stress responses was examined using hierarchical linear growth curve modeling. Results: A larger infant cortisol response to the heel-stick procedure was associated with exposure to elevated concentrations of maternal cortisol during the late second and third trimesters. Additionally, a slower rate of behavioral recovery from the painful stress of a heel-stick blood draw was predicted by elevated levels of maternal cortisol early in pregnancy as well as prenatal maternal psychosocial stress throughout gestation. These associations could not be explained by mode of delivery, prenatal medical history, socioeconomic status or child race, sex or birth order. Conclusions: These data suggest that exposure to maternal cortisol and psychosocial stress exerts programming influences on the developing fetus with consequences for infant stress regulation

Sensitization of cardiac responses to pain in preterm infants.

BackgroundPreterm infants are repeatedly exposed to painful experiences as part of their care in the neonatal intensive care unit. There is evidence from both animal and human studies that exposure to pain during the neonatal period may have persisting consequences for development.ObjectiveTo perform serial assessments of three heelstick blood draws to examine early changes both in physiological and behavioral responses to repeated exposure to painful stimuli in preterm infants.MethodsHeart rate and behavioral responses to three serially administered heelstick blood draws were evaluated in 22 medically stable preterm infants with less than 48 h of mechanical ventilation who were admitted to the neonatal intensive care unit.ResultsHeart rate and behavioral agitation significantly increased during each heelstick as compared to baseline. The heart rate response was larger to the third heelstick as compared to the first two procedures. Behavioral responses did not change across the three assessments.ConclusionsHealthy preterm infants sensitize to heelstick-induced pain, as measured by their heart rate responses. These data suggest that greater attention to the effects of repeated pain for the neonate is needed

Association between supraclavicular brown adipose tissue composition at birth and adiposity gain from birth to 6 months of age.

BackgroundBrown adipose tissue (BAT) is associated with higher energy expenditure and lower adiposity in adults. However, the relationship between BAT composition and adiposity in early life is unknown. The objective of this study was to test the hypothesis that brown fat composition at birth is prospectively associated with adiposity gain during the first 6 months of postnatal life.MethodsN=35 healthy infants were followed up prospectively from intrauterine life and birth through 6 months of age. Dixon magnetic resonance imaging (MRI) scans were conducted during the neonatal period to characterize supraclavicular BAT composition. Dual-energy X-ray absorptiometry to assess total body composition was performed within the first and sixth months of life.ResultsAfter adjusting for potential confounding factors, a more brown-like composition (smaller fat fraction) of the supraclavicular BAT depot was associated with a smaller increase in percent body fat over the first 6 months of postnatal life.ConclusionsA more brown-like BAT composition at birth appears to be protective against excess adiposity gain in early life. Newborn BAT tissue may constitute a target for prevention strategies against the subsequent development of obesity

Association between supraclavicular brown adipose tissue composition at birth and adiposity gain from birth to 6 months of age.

BackgroundBrown adipose tissue (BAT) is associated with higher energy expenditure and lower adiposity in adults. However, the relationship between BAT composition and adiposity in early life is unknown. The objective of this study was to test the hypothesis that brown fat composition at birth is prospectively associated with adiposity gain during the first 6 months of postnatal life.MethodsN=35 healthy infants were followed up prospectively from intrauterine life and birth through 6 months of age. Dixon magnetic resonance imaging (MRI) scans were conducted during the neonatal period to characterize supraclavicular BAT composition. Dual-energy X-ray absorptiometry to assess total body composition was performed within the first and sixth months of life.ResultsAfter adjusting for potential confounding factors, a more brown-like composition (smaller fat fraction) of the supraclavicular BAT depot was associated with a smaller increase in percent body fat over the first 6 months of postnatal life.ConclusionsA more brown-like BAT composition at birth appears to be protective against excess adiposity gain in early life. Newborn BAT tissue may constitute a target for prevention strategies against the subsequent development of obesity

The maternal cortisol awakening response in human pregnancy is associated with the length of gestation.

ObjectiveThe purpose of this study was to examine the relationship between intraindividual changes in cortisol responsiveness over pregnancy and the length of human gestation.Study designPregnancy-related changes in the cortisol awakening response (CAR), which is a measure of hypothalamic-pituitary-adrenal axis responsiveness, were assessed prospectively in 101 pregnant women at 16.8 +/- 1.4 weeks' and 31.4 +/- 1.3 weeks' (+/-SD) gestation. Cortisol was measured in saliva that was collected immediately and +30, +45 and +60 minutes after awakening.ResultsThe CAR was significant in pregnancy and exhibited progressive attenuation over the course of gestation. A larger CAR in late pregnancy and reduced attenuation of the CAR from early to late gestation were associated significantly with shorter gestational length.ConclusionThe findings are the first to suggest that the hormonal (cortisol) response to a naturally occurring challenge (awakening) and the degree of attenuation of this response over the course of gestation may represent a novel biomarker of increased vulnerability for earlier birth