Gestational stress influences cognition and behavior

Abstract

The developmental origins of disease or fetal programming model predicts that early exposures to threat or adverse conditions have lifelong consequences that result in harmful outcomes for health. The vast majority of the studies in support of the programming model in human beings are retrospective and most relied on surrogate measures of early experience such as birth weight or preterm birth. Recently, a small number of prospective studies have been reported that have documented the developmental consequences of exposures to stressful intrauterine conditions. These studies of gestational stress have clearly shown that fetal exposures to psychosocial and/or biological markers of adversity have significant and largely negative consequences for fetal, infant and child neurological development. Fetal exposure to stress, especially early in gestation, results in delayed fetal maturation and impaired cognitive performance during infancy and results in decreased brain volume in areas associated with learning and memory in children. The accumulating evidence supports the conclusion that fetal exposure to stress profoundly influences the nervous system, with consequences that persist into childhood and perhaps beyond.

Keywords: anxiety; corticotrophic-releasing hormone; cortisol; developmental origins of disease; fetal development; fetal programming; infant development; pregnancy; prenatal stress; sex difference; stress.

Figure 1.. The maternal perception of stress is influenced by many factors including genetics, social support and personality.

These factors may result in effective or maladaptive coping responses that determine, in part, the trajectory of maternal and placental stress hormones. Rapidly accelerating levels of stress hormones are related to adverse birth outcomes and, independently, to suboptimal development including negative temperament, impaired cognition and structural changes in the brain of the developing fetus. ACTH: Adrenocorticotropic hormone; CRH: Corticotrophic-releasing hormone.

Figure 2.. The regulation of the hypothalamic–pituitary–adrenocortical axis changes dramatically over the course of gestation with profound implications for the mother and the fetus.

One of the most significant changes during pregnancy is the development of the placenta, a fetal organ with significant endocrine properties. In nonpregnant women, exposure to stress activates a cascade of events including the release of CRH, ACTH and cortisol. This stress system is regulated by a negative feedback loop in which cortisol ‘turns off’ the HPA axis. During pregnancy, CRH is released from the placenta into both the maternal and fetal compartments. By contrast to the negative feedback regulation of hypothalamic CRH, cortisol increases the production of CRH from the placenta. Placental CRH (pCRH) concentrations rise exponentially over the course of gestation. Because of the positive feedback between cortisol and pCRH, the effects of maternal stress on the fetus may be amplified, representing one pathway by which stress may exert influences on the fetus. In addition to its effects on pCRH, maternal cortisol passes through the placenta. However, the effects of maternal cortisol on the fetus are modulated by the presence of a placental enzyme 11β-HSD2, which oxidizes it into an inactive form, cortisone. Activity of this enzyme increases as pregnancy advances and then drops precipitously so that maternal cortisol is available to promote maturation of the fetal lungs, CNS and other organ systems. A: Adrenal; ACTH: Adrenocorticotropic hormone; CRH: Corticotrophic-releasing hormone; H: Hypothalamic; P: Pituitary; pCRH: Placental corticotrophic-releasing hormone.

Figure 3.. A prospective protocol for the assessment of prenatal exposure to maternal stress and stress hormones on fetal, infant and child development.

Maternal psychosocial and biological stress measures are collected at five gestational intervals beginning at approximately 12 weeks. At 25, 31 and 36 gestational weeks, fetal neurodevelopment is evaluated with a standardized habituation/dishabituation paradigm. At delivery, length of gestation and birth weight are collected. Infant assessments begin at 24 h with the collection of cortisol and behavioral responses to the painful stress of the heel-stick procedure. Infant cognitive and neuromotor development, as well as stress and emotional regulation are evaluated at 3, 6, 12 and 24 months. Child neurodevelopment is assessed with cognitive tests, measures of adjustment and brain imaging between 5 and 8 years of age. GA: Gestational age.