While evidence linking prenatal stress to childhood allergy and wheeze continues to grow, underlying mechanisms remain poorly understood. Data largely from animal studies suggest that stress influences fetal development through disruption of key regulatory systems with particular focus on altered maternal and infant hypothalamic-pituitary-adrenal (HPA) axis functioning indexed by cortisol production. Stress-induced changes to the mother's HPA axis are thought to influence offspring risk in part through trans-placental passage of maternal hormones (e.g., cortisol) which may have programming effects on the child's HPA axis starting in utero and persisting after birth. Disrupted HPA functioning, either in mothers prenatally or in infants, may result in immune changes that predispose children to allergy or asthma. Thus, studies incorporating HPA axis measures in the prenatal and early postnatal period may provide insight into mechanisms involved in prenatal stress-elicited programming of early respiratory disease. Demonstrating whether the programming mechanism documented in animals is operating in humans has been more difficult due to unique challenges to assessing cortisol production in pregnant women and infants. In response to chronic stress, the HPA axis may operate at higher or lower levels than in normal homeostasis. Best methods for assessing the HPA axis in epidemiological studies remain unclear however. Research has relied largely on indices of salivary cortisol rhythms necessitating repeated measures, e.g., cortisol awakening response, diurnal cortisol slope, and daily output (area under the curve; AUC). Individual saliva samples reflect cortisol production over minutes to hours; salivary AUC and slope represent exposure over days. Salivary cortisol measures are also subject to situational variance due to mood states, stressors on sampling days, and other factors (e.g., sleep, physical activity). An integrated measure of cortisol levels from hair, which reflects level over weeks to months, has been proposed to capture more long term (trait-like) functioning of the HPA axis. Early evidence suggests that hair cortisol may be a valid measure of HPA axis functioning. While a one-time hair sample offers advantages, a major limitation is the loss of dynamic information provided with repeated saliva sampling. We propose that since these approaches tap into different aspects relevant to trait-like functioning of the HPA axis, a composite index incorporating both the integrated hair measure and information available from repeated saliva sampling may provide a better indicator of the hormonal milieu influencing fetal immune and lung development. These analyses will apply advanced statistical approaches to explore novel computational methods for characterizing chronic cortisol production in pregnant women and infants and assess whether they offer advantages over more conventional summary measures when modeling stress-elicited changes in HPA functioning as well as considering the derived cortisol biomarkers as predictors of child respiratory/allergic outcomes. This will be the first study to consider hair and salivary cortisol as a composite biomarker measure of prenatal stress effects.
In order to enhance our mechanistic understanding of how chronic prenatal stress contributes to adverse child respiratory health outcomes, we need valid and reliable biomarkers of stress effects. Establishing methods that more effectively characterize sustained stress-related shifts in HPA axis functioning (i.e., more fully characterizing dynamic production of cortisol) in mothers prenatally and their infants may be a major advance in understanding this central fetal programming mechanism. As disturbed functioning of the mother's HPA axis in pregnancy may influence programming of the infant HPA axis with consequent implications for a number of physical and psychological outcomes in children, findings from this study may have broad impact on the study of mechanisms linking prenatal stress to children's health as well as health impacts later in life.
