Over the past several years the UC Irvine Development, Health, and Disease Research Program has examined the interface between biological, behavioral, and social processes in human pregnancy, with a focus on the impact of maternal psychosocial stress and stress biology on fetal development, birth outcomes, and subsequent newborn, infant, and child developmental and health outcomes. Findings from our studies converge to suggest that after accounting for the effects of other established sociodemographic and obstetric risk factors, maternal psychosocial stress exposure is significantly and independently associated with increased risk of adverse pregnancy and birth outcomes related to the length of gestation (preterm birth) and fetal growth [low birth weight/small-for-gestational age (SGA) birth] [2
]. Our studies also suggest that the effects of maternal psychosocial stress are mediated, in part, by stress-related alterations in maternal–placental–fetal (MPF) endocrine and immune processes [6
]. Ongoing work in this area addresses the role of maternal–fetal gene–environment interactions, with a focus on candidate genes implicated in the regulation of key enzyme systems, steroid hormones and other peptides that regulate fetal development and birth outcomes. Other studies address the role of mitochondrial genetic variation, and the biobehavioral basis for the well documented racial/ethnic disparities and the Hispanic acculturation paradox in reproductive health outcomes. The significance of this area of research derives from the well established fact that adverse birth outcomes represent the major problem in maternal-child health in the USA and other developed and developing nations [10
A more recent set of studies, described below, has extended our research agenda to the long-term effects of prenatal psychosocial stress exposure on adult physiology and health. A large number of studies of fetal programming have focused on the critical role of prenatal and perinatal nutrition and have produced important findings and insights (reviewed in [11•
]). Based on the consideration that key environmental conditions that have shaped evolutionary selection include not only a variation in the amount and constituents of energy substrate availability and utilization (nutrition) but also conditions and challenges that may impact the physical integrity and survival of living organisms (stress), we and others have proposed that prenatal stress exposure likely represents yet another important adverse intrauterine environment that may impact the anatomy and physiology of the developing organism, with important implications for the developmental programming of health outcomes and disease susceptibility [12
]. Moreover, emerging evidence supports a bi-directional interaction between nutrition and stress, such that the consequences on target tissues of either one are moderated by the other [13
]. Last, we submit the application of a prenatal stress perspective which offers an excellent model system for the study of early development because it is increasingly apparent that the developing fetus acquires and incorporates information about the nature of its environment in part via the same systems that in an already-developed individual mediate adaptation and central and peripheral responses to endogenous and exogenous challenges [12
] (see conceptual framework in ).
Conceptual framework of a biobehavioral model in humans of prenatal stress-related maternal–placental–fetal endocrine and immune processes and programming of health and disease risk
Our studies are designed to address the primary question of elucidating the long-term health effects in adult human offspring of exposure to maternal psychosocial stress during pregnancy. Other corollaries addressed include whether these long-term effects are independent from those of other established obstetric, newborn, and childhood risk factors; whether the effects are outcome specific, or whether they influence a range of outcomes; and whether the effects are necessarily mediated by unfavorable birth outcomes. Experimental studies in animals suggest maternal exposure to psychosocial stress during gestation can independently exert long-term effects simultaneously on several central and peripheral systems in the offspring, and that titration of the prenatal stress exposure dose can produce significant long-term effects without altering the birth phenotype [18
]. However, only a very small number of studies have addressed these questions in humans.
As a first step to addressing these questions, we employed a retrospective case–control design in a sample of healthy young adults born to mothers with healthy pregnancies. One half of the study population of young adults was born to mothers who had experienced a major stressful life event during the index pregnancy (prenatal stress group), whereas the other half was a sociodemographically matched population with no history of maternal exposure to prenatal stress (comparison group). We selected a study population of younger as opposed to older adults in order to focus on predisease markers of physiological dysregulation of metabolic, endocrine and immune systems as early predictors of disease susceptibility. The potential effects of other established obstetric, newborn, and childhood risk factors on adult health were controlled using a stringent set of exclusionary criteria. Maternal and child medical records were obtained and screened to exclude presence of any maternal acute or chronic diseases, obstetric complications (e.g., gestational diabetes, hypertension/preeclampsia, infection), unhealthy behaviors (smoking), adverse birth outcomes (preterm birth, low birth weight), newborn complications, and history of any major childhood or current diseases (obesity, diabetes, asthma, and adverse neuro-developmental or psychiatric conditions). Study assessments were performed to quantify health and physiological markers of disease risk, including body composition and glucose-insulin metabolism (BMI and percentage fat mass; basal and postoral glucose tolerance test levels of glucose, insulin, leptin, adiponectin; fasting lipid profile), endocrine function (basal and post-behavioral/pharmacological stress levels of pituitary– adrenal stress hormones, chronobiological regulation of adrenal function, and assessment of HPA-axis feedback sensitivity), immune function [immune cell trafficking and lipopolysaccharide (LPS)-stimulated production of proinflammatory and anti-inflammatory and TH1/TH2 cytokines], and cognitive function (working memory under basal and hydrocortisone conditions). Because subtle physiological differences in disease susceptibility are often not detected in basal state we employed appropriate challenge tests to quantify the function of these systems under stimulated conditions (e.g., oral glucose challenge, ACTH stimulation test, LPS-stimulated immune responses).
Our results indicated that the young adults exposed during intrauterine life to maternal psychosocial stress consistently exhibited significant dysregulation of all these key physiological parameters, thereby placing them at increased risk for developing clinical disorders. Specifically, individuals in the prenatal stress group exhibited higher BMI and percentage body fat, primary insulin resistance, and a lipid profile consistent with the metabolic syndrome [23
], see ; altered immune function with a TH2
shift in the TH1
balance (consistent with increased risk of asthma and autoimmune disorders [24
]); altered endocrine function, with an increased adrenocorticotrophic hormone (ACTH) and reduced Cortisol levels during pharmacological and psychological stimulation paradigms (consistent with the high-risk endocrine profile exhibited by individuals exposed to early life abuse [25
]); and impaired prefrontal cortex (PFC)-related cognitive performance (impairments in working memory performance after hydrocortisone administration) [26
]. Consistent with the finding on cognitive function are results from one of our other recent prospective, longitudinal studies on the long-term effects of prenatal stress (anxiety) on child brain morphology. After excluding cases with low birth weight and adjusting for total gray matter volume, age, gestational age at birth, handedness and postpartum stress, maternal pregnancy-specific anxiety in mid-gestation was associated with gray matter volume reductions in several child brain regions, including the prefrontal cortex [27
Mean glucose, insulin, C-peptide, and leptin responses (±SEM) to an oral glucose tolerance test in prenatally stressed (PS, ‘black circles’) and comparison group (CG, ‘white triangles’) individuals (left panel)
Taken together, our findings suggest that in-utero exposure to prenatal psychosocial stress may confer increased long-term risk of a range of negative physiological and cognitive health outcomes in humans; these effects are independent from those of other established obstetric and childhood risk factors; and these long-term effects are not necessarily mediated by unfavorable birth outcomes. It is noteworthy that our above-described finding on body composition is consistent with a more recent report in a large, national cohort sample linking prepregnancy and prenatal stress exposure related to maternal bereavement to risk of childhood overweight [28
], and our finding on immune function is consistent with another recent report linking prenatal maternal anxiety with infant illnesses and antibiotic use [29