Alterations in stress responses of the hypothalamic-pituitary-adrenal axis in small for gestational age infants

Mounting epidemiologic evidence and animal models suggest that stressful conditions during the intrauterine period may increase susceptibility to several adult conditions, including metabolic syndrome, cardiovascular disease, and psychiatric disorders. Increased cortisol levels due to alterations in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis are believed to be one mediating mechanism. Infants born after significant exposure to stressful conditions are often small for gestational age (SGA) based on standardized growth norms. Lifelong programming of the HPA axis has been proposed as a mechanism to explain the association between SGA infants and adult disease. However, few studies have measured HPA axis function proximal to birth as done in this study of SGA infants during the first week of life. Participants included 37 infants in two groups based on birth size (gestational age range: 34-41weeks). SGA infants were <10th percentile for age (n=21) and appropriate for gestational age (AGA) infants (n=16) were from 20 to 90th percentile for age. Cortisol response to a heel lance for blood collection was measured for all infants. Hierarchical Linear Modeling was used to test the effect of AGA/SGA group status on cortisol trajectories in response to the stressor. Group was a significant predictor of quadratic slopes (t=2.84, χ²=8.19, p=004) after controlling for the effect of group on intercepts and linear slopes. Predicted growth curves for ln-cortisol were plotted for each group based on regression coefficients. The predicted curves capture the significant group difference in trajectories, as well as the blunted response for the SGA group and the robust peak in cortisol production in response to the stressor for the AGA group. This evidence suggests SGA neonates have blunted HPA axis responses to stressors in comparison to AGA infants. These findings are consistent with animal models showing that adverse intrauterine conditions can result in blunted cortisol responses to acute stressors and may provide a mechanism for adult susceptibility to disease for individuals that are SGA at birth.