Stress regulating systems and their role for an intrauterine origin of diseases

There is evidence that adverse conditions during intrauterine development affect future health of the offspring. Hypothalamus-pituitary-adrenal (HPA) axis dysregulation is assumed to play an important role in the association of small for gestational age (SGA) and the pathogenesis of hypertension and the metabolic syndrome. Stress response patterns in SGA neonates may identify a link with intrauterine-induced permanent maladaptation of the HPA axis. Salivary cortisol and cortisone levels were therefore analyzed during resting conditions and in response to a pain-induced stress event in SGA ( 5th percentile) and appropriate for gestational age (AGA) neonates born 34 wk of gestation. In AGA neonates, salivary cortisol and cortisone levels significantly increased after the stress event (p 0.05). In contrast, SGA infants exhibited a blunted steroid release after stress induction (p 0.76, p 0.65, respectively). No influence of mode of delivery (p 0.93), gender (p 0.21), and gestational age (p 0.57) on stress response patterns was observed in a multiple stepwise regression. SGA neonates show a blunted physiologic activation of the HPA axis in response to a stress stimulus. Thus, intrauterine-induced alteration of HPA axis regulation seems to persist into the postnatal period and represents a prerequisite for the hypothesis of HPA axis involvement in the fetal origin of adult diseases. (Pediatr Res 65: 231–235, 2009) Substantial evidence from epidemiologic data and experimental animal models indicate that stressful conditions during intrauterine fetal life affect behavioral development and future health of the offspring. Maladaptation of the fetal autonomic regulation has been suggested as a putative predisposing factor in the pathogenesis of cardiovascular, metabolic, and psychiatric diseases in low birth weight (LBW) infants (1–3). This has been reinforced by the discovery of an early programming of the stress response–mediating neuroendocrine system, namely the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (4,5). As such, LBW, a surrogate for fetal malnutrition has been linked with increased adrenocortical hormone activity and activation of the sympathetic nervous system (6–9) in childhood and adult life in independent populations. A pathophysiologic explanation of this phenomenon described by Barker’s group as “fetal programming” (10) has been derived from animal models revealing long-term changes in the molecular expression of steroid receptors within the limbic system (11). Increases in glucocorticoids, such as cortisol and cortisone, are generally considered as adaptive mechanisms to mobilize energy for survival in response to a stressful event or to danger (12). Prolonged intrauterine exposure to stress, however, may lead to an alteration of the set point of the stress regulatory system resulting in increased levels of cortisol that can negatively effect the functioning of several biologic systems (13,14) and ultimately result in arterial hypertension and diabetes mellitus type II, one of the main risk factors for arteriosclerosis-associated diseases. Because patterns of stress response in early postnatal life may help to identify prenatally induced alterations in the HPA axis and simultaneously exclude an only temporarily activated HPA axis due to adverse intrauterine conditions, we analyzed the stress reactivity of the HPA axis in small for gestational age (SGA) newborns. Our results provide evidence that the HPA axis is already altered in SGA newborns and may, if these alterations persist permanently, play a role in the intrauterine origin of adult diseases. MATERIALS AND METHODS Subjects. The study was approved by the Research Ethics Committee of the University of Zurich and the Federal Ethics Commission of the Canton of Zurich. Written maternal consent was obtained from all participants in the study. Saliva samples from 40 appropriate for gestational age (AGA) and 18 SGA infants were analyzed. Approximately, 40 SGA infants after 34 wk of gestation were born during the study period (April–September, 2005) in our hospital with 2300 deliveries per year. Healthy controls were recruited until approximately the double number of study patients was reached to obtain adequate numbers for statistical evaluation. SGA was defined as birth weight below the 5th percentile of the gender-specific newborn reference chart (15). Birth weight between the 10th and 90th percentile was required for AGA children. Only healthy newborns delivered after 34 wk of gestation ( 238 d) were included in the study. Newborns requiring intensive care or those with malformations were excluded from the study. Additional exclusion criteria included maternal substance abuse (nicotine, alcohol) and exogenous corticosteroid treatment (e.g., for lung maturation induction) during pregnancy. Sonographic measurements of fetal crown-rump length and biparietal diameter during the first trimester served as parameters for accurate determination of gestational age. In the SGA group, 10 infants had a diagnosis of intrauterine growth restriction (IUGR) established either by serial sonographic biometry or by pathologic Doppler measurements, one was SGA alone and 7 infants were referred to our clinic for delivery only and did not receive antenatal care at our institution. Sonographic data for the latter group were not available. Experimental procedures. Salivary cortisol and cortisone levels were collected between 72 and 96 h postnatal during a routine heel prick for the Guthrie test (a newborn screening test for metabolic disorders). This was considered to be the equivalent of a stress event. Although infants are born Received June 11, 2008; accepted September 18, 2008. Correspondence: Leonhard Schäffer, M.D., Universitäts-Frauenklinik, Frauenklinikstrasse 10, CH-8091 Zürich, Switzerland; e-mail: leonhard.schaeffer@usz.ch Abbreviations: AGA, appropriate for gestational age; HPA axis, hypothalamus-pituitary-adrenal axis; SGA, small for gestational age 0031-3998/09/6502-0231 PEDIATRIC RESEARCH Vol. 65, No. 2, 2009 Copyright © 2009 International Pediatric Research Foundation, Inc. Printed in U.S.A.