Objective-Prenatal exposure to inappropriate levels of glucocorticoids 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' 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 exert programming influences on the developing fetus with consequences for infant stress regulation.The prenatal period is a time of enormous change during which organs and organ systems are forming and are susceptible to both organizing and disorganizing influences. These influences on the fetus have been described as programming; the process by which a stimulus or insult during a vulnerable developmental period has a long-lasting or permanent effect. The effects of programming are dependent on the timing (i.e. the developmental stage of organ systems and the changes in maternal and placental physiology) and the duration of exposure (E.P. Davis & Sandman, 2010; Nathanielsz, 1999). Compelling evidence from epidemiological studies indicates that adverse birth outcomes such as low birth weight and preterm birth are associated with a number of diseases of adulthood including heart disease and obesity (Barker, 1998(Barker, , 2002 as well as psychological dysfunction (Bohnert & Breslau, 2008;Costello, Worthman, Erkanli, & Angold, 2007). The influence of prenatal exposure to maternal stress signals on the developing fetal HPA axis has been proposed as one mechanism that underlies fetal programming of adult health outcomes (Kapoor, Petropoulos, & Matthews, 2008;Seckl, 2008 Glucocorticoids are steroid hormones that exert influences on nearly every organ and tissue in the body (Drake, Tang, & Nyirenda, 2007). Regulation of the maternal HPA axis changes dramatically during the course of normal human pregnancy. Maternal cortisol inc...

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.

The hypothalamic-pituitary-adrenocortical (HPA) axis is a major neuro-endocrine pathway that modulates the stress response. The glucocorticoid, cortisol is the principal end product of the HPA axis in humans, and plays a fundamental role in maintaining homeostasis and in fetal maturation and development. Antenatal administration of synthetic glucocorticoids (GCs) accelerates fetal lung maturation and has significantly decreased neonatal mortality and morbidity in infants born before 34 weeks of gestation. Exposure to excess levels of endogenous GCs and exogenous GCs (betamethasone and dexamethasone) has been shown to alter the normal development trajectory. The development and regulation of the fetal HPA axis is discussed and the experimental animal evidence presented suggests long-term adverse consequences of altered HPA function. The clinical data in infants exposed to GCs also suggests altered HPA axis function over the short term. The longer-term consequences of antenatal GC exposure on HPA axis function and subtler neurodevelopmental outcomes including adaptation to stress, cognition, behavior, and the cardiovascular and immune responses are poorly understood. Emerging clinical strategies and interventions may help in the selection of mothers at risk for preterm delivery who would benefit from existing or future formulations of antenatal GCs with a reduction in the associated risk to the fetus and newborn. Detailed longitudinal long-term follow up of those infants exposed to synthetic GCs are needed.

The objective of this study was to determine the consequences for HPA axis functioning among healthy full-term newborns of prenatal treatment with the synthetic glucocorticoid (GC), betamethasone, which is the routine treatment for threatened preterm delivery. Ninety full-term infants were recruited into two study groups (30 betamethasone treated; 60 comparison group matched for GA at birth and sex). The cortisol and behavioral response to the painful stress of a heel-stick blood draw was assessed 24 hr after birth. Full-term infants exposed to prenatal betamethasone displayed a larger cortisol response to the heel-stick procedure, despite no differences in baseline levels. Further, within the recommended window of betamethasone administration (24-34 gestational weeks), infants exposed to betamethasone earlier in gestation displayed the largest cortisol response to the heel-stick. These data add to accumulating evidence that prenatal exposure to elevated GCs programs the development of the HPA axis. ß 2010 Wiley Periodicals, Inc. Dev Psychobiol 53: 175-183, 2011.

The 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.