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Curt A Sandman†1 & Elysia P Davis1,2 333 City Drive West, Suite 1200, Department of Psychiatry & Human Behavior, University of California, Irvine, Orange, CA 92868, USA 2 Department of Pediatrics, University of California, CA, USA † Author for correspondence: n Tel.: +1 714 940 1923 n Fax: +1 714 940 1939 n [email protected] 1

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 rely 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. Programming influences on development

Each developing organism plays an active role in its own construction. To accomplish this task, the fetus collects information from its maternal host to prepare for postnatal survival. If the information received by the fetus indicates that the environment is stressful or that the host is impaired, the fetus adjusts its developmental trajectory and/or modifies its nervous system to ensure survival in a potentially hostile environment [1–6] . One vivid example of this is the metamorphic adjustment made by the tadpole in response to the stress of an evaporating pool of life-sustaining water [2,7,8] . The desert-dwelling western spadefoot toad lays its eggs in pools of desert rainwater. If tadpoles detect that the conditions for normal development and survival are unfavorable or hostile (e.g., rapid evaporation of the pool), a cascade of stress hormones including corticotrophic-releasing hormone (CRH) and corticosterone are released. These hormones act both centrally and peripherally to influence metabolism and can accelerate development and metamorphosis so the tadpole can escape the desiccating environment and avoid imminent peril. If the biological stress response is blocked during environmental desiccation, the rate of development is arrested and the tadpole’s survival is compromised. There are long-term consequences of accelerated development for the tadpole that survives this stressful challenge because it is smaller 10.2217/FNL.10.35 © 2010 Future Medicine Ltd

at maturity and is at a disadvantage when competing with a normally developing toad foraging for food or reproducing. The human fetus has also evolved mechanisms to acquire information about the environment and guide its development. The human placenta is both a sensory and effector organ that incorporates and transduces information from its maternal host environment into the fetal developmental program. The fetal/placental unit’s early detection of stress signals from the maternal environment (e.g., cortisol) ‘informs’ the fetus that there may be a threat to survival. This information may prime or advance the placental clock [9] by activating the promoter region of the CRH gene and increasing the placental synthesis of the ‘master’ stress hormone, CRH [10] . The rapid increase in circulating CRH begins the cascade of events resulting in myometrial activation and, in extreme cases, fetal escape from a malignant environment. Early departure (i.e., preterm birth) from the inhospitable host environment may be essential for survival, but it also may have grave consequences for the human fetus just as it does for the tadpole. Human infants born early suffer a panoply of motor, sensory and neurological impairments that persist for a lifetime (Figure 1) [11–13] . Preterm birth is one potential outcome of fetal exposure to stress during gestation; however, there are other lifelong consequences of Future Neurol. (2010) 5(5), 675–690

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Gestational stress influences cognition and behavior

Keywords anxiety n corticotrophicreleasing hormone n cortisol n developmental origins of disease n fetal development n fetal programming n infant development n pregnancy n prenatal stress n sex difference n stress n

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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.

exposure to intrauterine or gestational sources of stress. Prenatal life is a time of unprecedented growth, and because of this, the human fetal nervous system is particularly vulnerable both to organizing and disorganizing influences. Aversive intrauterine events imprint a pattern of activity that results in a ‘program’ of disorders. These programs influence health and the subsequent behavioral and physio logical repertoire of the individual [10,14] . Retrospective studies have concluded that fetuses exposed to maternal stress at various times during gestation are at greater subsequent risk for later cardiovascular disease, hypertension, hyperl ipidemia, insulin resistance, noninsulin-dependent diabetes mellitus, obesity, higher serum cholesterol concentrations, 676

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shortened lifespan and other poor health outcomes [14–18] . These influences on the fetus have been described as ‘programming’. Programming is a process by which a stimulus or insult during a critical developmental period has a long-lasting or permanent influence. Because tissues develop in a specific sequence from conception to maturity, different organs are sensitive to environmental influences at different times depending upon their rate of cell division. Thus, the timing of the stress during development coupled with the timetable for organogenesis determines the nature of the programmed effect. Regardless of the developmental timetable for organ development, compensations in response to stress are made by the fetus to spare the brain. However, compensation has a price. For instance, stress may decrease the blood supply available to the fetus. To protect the brain, blood is shunted from peripheral organs to nurture the fetal nervous system. This adaptation has an irreversible price that may include damage to relatively expendable peripheral organs and damage to the fetal nervous system because the vulnerable fetal brain cannot escape the circulating biochemical fingerprint of maternal stress. Physiology of gestational stress

Physiological stress systems change dramatically during pregnancy (Figure 2) . It is important to acknowledge that the differences in reproductive and stress physiology, even in very closely related species such as humans and nonhuman primates, limit the validity of generalizing from animal models [19] ; thus, this article will focus only on studies of gestational stress in human subjects. Normally, stress activates the expression of the master stress hormone, hypothalamic CRH, which travels down the median eminence and stimulates the synthesis and release of adreno corticotropic hormone (ACTH) from the anterior pituitary. The release of ACTH into the bloodstream triggers the release of cortisol from the adrenal gland, preparing the organism for ‘fight or flight’. Under normal circumstances, this hypothalamic–pituitary–adrenocortical (HPA) system is under the control of negative feedback regulation so that the presence of high levels of cortisol in the bloodstream will turn off the hypothalamic and pituitary stress systems. This system is altered dramatically during pregnancy because the placenta expresses the genes for CRH (hCRH mRNA) and pro-opiomelanocortin, the precursor for ACTH and b-endorphin. All of these stress hormones increase as pregnancy advances, but the future science group

Gestational stress influences cognition & behavior

exponential increase in placental CRH (pCRH) in maternal plasma is especially dramatic, reaching levels observed only in the hypothalamic portal system during physiological stress [20] . pCRH is identical to hypothalamic CRH in structure, immunoreactivity and bioactivity. However, there is one crucial difference in the regulation of hypothalamic CRH and pCRH. By contrast to the negative feedback regulation of hypothalamic CRH, cortisol stimulates the expression of hCRH mRNA in the placenta, establishing a positive feedback loop that allows

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for the simultaneous increase of pCRH, ACTH and cortisol over the course of gestation [21,22] . As pregnancy advances towards term and these stress hormones increase, the positive feedback loop becomes dampened as the hypophyseal corticotrophs are downregulated [23,24] . These changes have dramatic implications for the human fetus and for the mother. First, because of the dramatic changes in stress hormones during pregnancy (there are also vascular and immunological changes consistent with stress), pregnancy can be considered a major

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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. 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 the placental enzyme 11b‑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: Adrenocortical; ACTH: Adrenocorticotropic hormone; CRH: Corticotrophic-releasing hormone; H: Hypothalamic; P: Pituitary; pCRH: Placental corticotrophic-releasing hormone.

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physiological stressor. Second, because of the positive feedback between cortisol and pCRH that develops during human pregnancy, the effects of maternal stress on the fetus may be amplified. The fetus will be exposed simultaneously to both increases in maternal cortisol and pCRH. Third, because the receptors in the maternal stress system are downregulated as pregnancy advances, the communication between the hypothalamic and pituitary axis is partially blocked. As a result, during late gestation, environmental stress is less effective in triggering the endocrine axis and women become less responsive to the effects of stress [24–29] . Thus, stressful events early in pregnancy are experienced by the mother as more unpleasant and may exert greater influences on the fetus than events closer to term. The increase in stress hormones and the change in perceptions of stress during gestation play a fundamental role in the organization of the fetal nervous system and in maternal adaptation during pregnancy. The precise mechanisms of communication of stress between the mother and fetus are unknown. There is evidence for a positive �� correlations between maternal cortisol and fetal cortisol [30] and maternal cortisol and amniotic fluid cortisol [31] after controlling for circadian variation and other medical factors. These results suggest that maternal levels of cortisol are present in the fetal environment and may therefore be a reasonable surrogate marker for fetal exposure. A more direct index of fetal exposure to stress may be pCRH. Increases in pCRH provide evidence that the fetus has experienced and responded to a stress signal (Figure 2) . pCRH is the biological stress index most consistently associated with birth outcomes [9,10,32] , but it has not been used extensively to predict neurodevelopmental outcomes (but see [33,34]). Future research should capitalize on this direct index of fetal experience that avoids the pitfalls associated with assuming that maternal stress results in a coherent and consistent maternal physiological profile that is transmitted to and transduced by the fetus. Why the effects of gestational stress are sensitive to timing

The consequences of stress for the developing fetus will be determined by a multitude of factors, including: The timetable for fetal organogenesis;

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The timetable of fetal development will render different systems vulnerable to influence at different gestational periods. Between the gestational ages of 8 and 16 weeks, migrating neurons form the subplate zone, awaiting connections from afferent neurons originating in the thalamus, basal forebrain and brainstem. Once neurons reach their final destination at approximately the 16th fetal week, they arborize and branch in an attempt to establish functional connections [35] . It is plausible that stress early in gestation will disrupt processes related to neural migration. During the last third of human pregnancy, the fetal brain is forming secondary and tertiary gyri and exhibiting neuronal differentiation, dendritic arborization, axonal elongation, synapse formation and col lateralization and myelination [36,37] . Synapse formation during this period accelerates to a rate of approximately 40,000 synapses per minute [36] . Later gestational stress may have the greatest effect on connectivity between regions and synapse formation. Timing effects also result from changes in maternal and placental stress physiology. Concentrations of the major stress hormones rise with advancing gestation and these changes have consequences for fetal exposure [30] . The effects of these hormones are modulated by the activities of binding proteins and enzymes. For example, concurrent with increases in pCRH, maternal CRH binding protein rises and then falls abruptly at approximately the 36th week of gestation [9] . The levels of binding protein may moderate the activity and the effects of the pCRH molecule on the fetal nervous system. Maternal plasma cortisol-binding globulin (CBG) levels also change across pregnancy. CBG is stimulated by estrogen and levels increase progressively with advancing gestation until 36 gestational weeks, when there is a significant decline in CBG [38] . Variations in CBG may contribute to individual differences in developmental outcomes because levels have been shown to be lower in women with growth-restricted fetuses [38] . Another gestational timing effect may relate to the activity of the placental enzyme 11b‑HSD2. This enzyme oxidizes maternal cortisol into cortisone [39,40] , inactivating it and protecting the fetus from its direct and sometimes harmful effects during critical periods of development [41] . The levels of placental 11b-HSD2 rise as gestation progresses before falling precipitously near term, ensuring maturation of the fetal lungs, CNS and other organ systems in full term births [42,43] . Despite future science group


the presence of this protective enzyme early in gestation, maternal cortisol does reach the fetus and the amount varies with circulating maternal levels [30,31] . Furthermore, elevated maternal stress downregulates 11b-HSD2 activity in the placenta, allowing a greater proportion of maternal cortisol to cross the placenta and so to reach the fetus [44] , with negative consequences for fetal growth and development [40,45] . This is another mechanism whereby the consequences of maternal stress for the developing fetus may be amplified. Indeed, the correlation between maternal cortisol and amniotic fluid cortisol is higher among anxious compared with nonanxious women, although cortisol levels do not differ between the two groups [46] . Because of the timetable of fetal development and the changes in maternal and placental physiology, the consequences of stress exposures will vary based on the gestational period of exposure. These physiological changes result in a dampening of maternal responses to environmental stress, and these changes in maternal perception of stress are another factor that will influence gestational timing. Elevated circulating stress hormones coupled with decreased psychosocial responses to stress as pregnancy advances create a paradoxical situation that might explain why psychological and biological markers of stress during pregnancy exert independent effects on outcome [47] . Gestational stress influences the human fetus

In humans, the most well-documented effects of exposure to maternal stress are on birth outcomes, including preterm delivery [26,48,49] and the resulting adverse developmental consequences [13] . However, it is believed that intrauterine exposures, including stress, contribute to these developmental impairments independently of preterm birth or growth restriction. The study of human fetal behavior is important since it provides the opportunity to assess the effects of gestational stress on development before the effects of external forces, such as birth outcome, parenting and socialization, are exerted. Several studies reported that increased maternal anxiety or stress is associated with hyperactive fetuses and fetal tachycardia [50,51] , a sudden fall in fetal heart rate (FHR) followed by over-swing recovery [52,53] , significant FHR increases [54] , increased fetal motor activity [55] , more time in quiet sleep [56] and higher pulsatility index in the fetal middle cerebral artery [57] . Conversely, reduced anxiety or positive feedback future science group

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results in decreased fetal breathing and increased body movements [58,59] . Ultrasound examination of 28 panic-stricken women between 18 and 36 weeks of gestation (after an earthquake) indicated that all fetuses showed intense hyperkinesia lasting between 2 and 8 h, with numerous, disordered and vigorous movements [60] . These studies provide compelling evidence that maternal stress has direct and immediate effects on fetal physiology and behavior. Direct measures of fetal responses to external stimulation provide an index of fetal nervous system development and have been used to assess the developmental consequences of exposure to biological and psychosocial indices of stress [61] . With measures of FHR, we discovered that fetuses of women with elevated pCRH during the third trimester were less responsive to the presence of a novel stimulus [62] . In a subsequent study, we reported that FHR habituation was delayed when fetuses were exposed to ‘unbalanced’ expression of the HPA axis (i.e., overexpression of endogenous opiates and underexpression of ACTH) and was accelerated (i.e., better learning) when there was balanced expression of maternal ACTH and endogenous opiates [63] . These studies indicate that there are concurrent associations between stress hormone profiles and fetal behavior. However, programming influences should reflect temporal patterns in which the consequences of gestational stress are apparent at a later time. We showed that low pCRH at 15 gestational weeks, but not later, predicted a more mature FHR pattern at 25 gestational weeks [64,65] . This may be the first uncontaminated evidence of gestational stress exerting programming influences on the nervous system that was completely independent of postnatal experiences. Gestational stress influences infant development

Although there are a large number of studies documenting lifelong consequences of prenatal stress with animal models, much less is known about the consequences for human development. Results from animal models have established that fetal exposure to stress is associated with compromised neurodevelopment, enhanced stress reactivity and increased fearful or anxious behavior [66–73] . Human studies have focused primarily on the consequences of prenatal stress for behavioral and emotional regulation. Prenatal exposure to elevated levels of maternal psychosocial stress and stress hormones is www.futuremedicine.com

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associated with behavioral and emotional disturbances during infancy and childhood that are independent of birth outcome and postpartum maternal stress or depression [33,74–81] . Fewer studies have examined the effects of prenatal stress on cognitive development. Evidence is emerging that assessment of stress specific to pregnancy is a stronger predictor of infant and child neurodevelopmental outcomes compared with that of generalized stress. Although there is evidence that maternal self-report of elevated stress, depression and anxiety during the prenatal period is associated with delayed infant cognitive and neuromotor development [78,82] and that these deficits may persist into adolescence [83] , the findings across studies are not consistent [84,85] . It is possible that generalized self-report measures of psychological distress do not adequately characterize stress that is unique during pregnancy. Measures of stress that are related to issues about pregnancy (e.g., “I am fearful regarding the health of my baby”; “I am concerned or worried about losing my baby”; and “I am concerned or worried about developing medical problems during my pregnancy”) appear to be better than measures of generalized psychological distress for predicting neurodevelopmental outcomes including fetal behavior [86] , infant cognitive and motor development [47,82,84] and brain development [87] . There is evidence that fetal exposure to maternal and placental stress hormones influences temperament [33,76,79] . Much less is known about the consequences for infant and child cognitive and neuromotor development. One group reported that fetal exposure to elevated maternal cortisol during the third trimester was associated with delays in mental development in a small group of infants at 3 months of age and motor development at 3 and 8 months of age [82] . In the largest study conducted (125 subjects) with repeated evaluations at five prenatal intervals and three intervals during infancy (F igur e 3) , we reported that the consequences of fetal exposure to maternal cortisol and pregnancy-specific anxiety were dependent on when during gestation these two indicators of stress were elevated [47] . Fetal exposure to cortisol early in pregnancy resulted in significantly lower scores on measures of mental development. Conversely, elevated maternal cortisol late in gestation was associated with signi ficantly higher scores on measures of mental development. Similar results were observed for levels of maternal pregnancy-specific anxiety. Despite the similar effects of maternal cortisol 680


and anxiety on infant cognition at 1 year of age, these two measures of stress were not found to be related and exerted independent effects on developmental outcomes. These findings linking cortisol to infant cognitive development are remarkably consistent with its function in the maturation of the human fetus. Early in pregnancy, the fetus is protected from the naturally occurring increases in maternal cortisol by 11b-HSD2 (Figure 2) . However, because 11b‑HSD2 is only a partial barrier, excessive increases in maternal cortisol early in gestation will expose the fetus to ‘toxic’ levels with potentially detrimental consequences. By contrast, as pregnancy advances towards term, exposure to elevated cortisol is necessary and beneficial for maturation of fetal organ systems including the fetal CNS and lungs [88] . Fetal exposure to increased cortisol during the third trimester is facilitated by the sharp drop in 11b‑HSD2, which allows a greater proportion of maternal cortisol to cross the placental barrier [89,90] . Early in gestation, exposure to high levels of cortisol has damaging and persisting effects on the brain and behavior. Towards the end of gestation, when elevated levels of cortisol are required for maturation, exposure to high levels has beneficial effects on the brain and behavior. The findings of the Davis and Sandman study were observed in a healthy low-risk cohort of children born at term and remained significant after considering an extensive list of prenatal and postnatal controls (including birth outcome and postnatal maternal stress and depression) [47] . The consequences for the infant were confined to cognitive outcomes – motor performance was unaffected by either exposure to cortisol or maternal anxiety. As described later, it is probable that the effects of cortisol and anxiety are specific to cognition because areas of the brain, especially the hippocampus [73,91] , are most vulnerable to prenatal exposure to cortisol and stress. Gestational stress exerts influences on the developing brain during childhood

Low birth weight and preterm birth have been related to reductions in regional brain volumes [12,92–95] . However, because adverse birth outcomes may be markers of in utero stress exposure (Figure 1) , the changes in brain morphology may be due to perinatal complications and not birth phenotype. Recently, our group published the first study to show that fetal exposure to pregnancy-specific anxiety was future science group


related to specific changes in brain morpho logy at 6–9 years of age, independent of birth phenotype [87] . Specifically, pregnancy-anxiety early in gestation was associated with gray matter volume reductions in the prefrontal cortex, the premotor cortex, the medial temporal lobe, the lateral temporal cortex and the postcentral gyrus, as well as the cerebellum extending to the middle occipital gyrus and the fusiform gyrus. These brain regions are associated with a variety of cognitive functions. Specifically, the prefrontal cortex is involved in executive cognitive functions such as reasoning, planning, attention, working memory and some aspects of language [96] . Structures in the medial temporal lobe, including areas connected to the hippocampus (e.g., entorhinal, perirhinal and parahippocampal cortex), constitute a medial temporal lobe memory system [97] . The temporal polar cortex is involved in social and emotional processing, including recognition and semantic memory [98,99] . A network in the temporal–parietal cortex consisting of the middle temporal gyrus, the superior temporal gyrus and the angular gyrus has been shown to be important in processes related to auditory language processing in children [100] . Brain systems involved in language learning including

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the inferior frontal gyrus, the middle temporal gyrus and the parahippocampal gyrus are also reduced in children ‘exposed’ to high levels of pregnancy anxiety [101] . This is the first prospective study in healthy children to show that prenatal maternal anxiety is related to distinctive patterns of structural brain development. These morphological patterns may increase vulnerability for certain neurodevelopmental disorders and impair cognitive function. Mechanisms of stress effects on the developing nervous system

Exposure to prenatal maternal stress has parallel and direct effects on the fetal brain and on fetal endocrine systems. These two effects respectively influence cognition and emotion and ultimately cooperate in producing longterm effects on the behavior and physiology in the offspring [102] . Evidence from animal models for persistent organizational changes or programming influences on the nervous system has been growing [103] and may include changes in neurotransmitter levels [104–106] , cell growth and survival [105,107–109] and adult neurogenesis [73,110–113] . For instance, at high concentrations, the stress hormones CRH and cortisol may inhibit growth and differentiation Assessment protocol

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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.



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of the developing nervous system. Considerable evidence indicates that glucocorticoids, such as cortisol, are neurotoxic to hippocampal CA3 pyramidal cells [114–116] , and fetal exposure to high levels of glucocorticoids produces irreversible damage to the hippocampus [91,117] . Similar neurotoxic effects are observed with exposure to high levels of CRH. Exogenously administered CRH increases neuronal excitation, leading to seizures in limbic areas associated with learning and memory [118–120] , and may participate in mechanisms of neuronal injury [121,122] . The precise mechanisms by which early-life stress provokes long-term effects on cognition are not resolved, but the evidence is clear that areas critical for learning, including the hippocampus, are influenced by exposure to prenatal stress and stress hormones. One lingering question is whether or not the effects of maternal responses to stress on the fetus are related to some shared genetic factor. In the studies of naturally occurring variations in maternal stress, it is difficult to separate the association between elevated maternal cortisol or predisposition to respond to stress and the neurodevelopmental patterns observed in the fetus and child from the consequences of other factors that might contribute to this asso ciation, such as shared genes. However, the programming findings reported here are consistent with animal models in which random assignment is possible [123] and with human studies that evaluated the consequences of a randomly occurring traumatic events, such as natural disasters [124,125] . Furthermore, recent human studies have documented developmental consequences of prenatal stress among children conceived by in vitro fertilization that were not genetically related to their mother [126] . Thus, genetic mechanisms cannot be completely ruled out on experimental grounds as a possible explanation for the effects of maternal experience on fetal/child development. However, there is reasonable evidence to warrant the conclusion that maternal stress is translated into direct effects on the fetal nervous system. Sex-specific programming effects

There is a rapidly expanding literature in animal models indicating that there are sexually dimorphic responses to stress and adversity [127,128] including and perhaps especially associated with stress during the prenatal period [129–131] . In the study of human FHR responses to external stimulation reported previously [64] , we discovered that female fetuses 682


displayed more mature responses than males at 31 and 37 gestational weeks. These findings are consistent with findings of sex-specific trajectories of fetal development [132,133] and the sexually dimorphic risk of neurological impairment associated with neonatal complications [134] . In general, these findings and others [135] indicate that males are more vulnerable to developmental insults, including prenatal adversity, than females. There is evidence that sexually specific patterns are formed very early in development and are reflected in the function and response to stress of the placenta. The female placenta appears to be more responsive to changes in glucocorticoid concentration than the male placenta. Clifton has argued that this sexually dimorphic placental sensitivity to signals of adversity (elevated glucocorticoids) results in different patterns of response and in parti cular in different patterns of growth [136] . Male fetuses, Clifton suggests, do not alter their patterns of development in response to adversity and continue to grow despite reduced resources. Since the male fetus has not adjusted to the initial adversity and has not conserved its resources, it is more susceptible to later stress, with increases in morbidity and mortality. By contrast, the female placenta responds or adjusts to an adverse maternal environment in multiple ways (e.g., gene and protein changes) resulting in reduced growth. If exposed to stresses later in gestation that reduce nutrients and resources, the female fetus has conserved its energy needs, which increases the probability of survival. By this mechanism, sexually specific patterns of response to stress may be programmed very early in fetal development. Prenatal & early postnatal influences on development

There is a growing consensus from work with humans that prenatal maternal stress and stress hormones have consequences for developmental outcomes and that these associations cannot be accounted for by the postnatal environment. However, it is highly plausible that the prenatal and early postnatal environment will act synergistically to shape developmental trajectories. Factors such as socioeconomic status (SES) and quality of the caregiving environment might moderate the effects of prenatal stress exposures. There are well-documented associations between poverty, lower SES and neurocognitive performance [137] . Moreover, there is evidence for relationships between future science group


neonatal stress reactivity and maternal SES [138] . Although studies documenting an influence of prenatal stress on development have controlled for the contribution of SES, the possibility that SES moderates the influence of prenatal stress remains. For example, the effects of prenatal stress may be amplified in the context of an impoverished postnatal environment. An additional factor that is likely to modify the consequences of prenatal stress is the quality of early postnatal maternal care. High-quality maternal care positively influences a wide range of developmental outcomes including social competence [139–144] , emotional regulation and temperament [145,146] , as well as cognitive and language development [147–151] . Few human studies have evaluated the joint role of the prenatal and early postnatal environment for shaping developmental trajectories. One possibility is that a high-quality postnatal environment will reverse the negative effects of prenatal stress. There is compelling evidence from animal models that the negative effects of prenatal maternal stress can be attenuated by high-quality postnatal maternal care [152–155] . Consistent with these studies, there are a few recent studies with humans that suggest that the provision of high quality maternal care may ameliorate the negative effects of prenatal stress on fearful tempera ment [156] , stress regulation [80] and cognitive functioning [157] . It is plausible that the postnatal environment compensates or exaggerates the effects of prenatal stress. Alternatively, it is possible that the prenatal environment prepares the infant for adaptation to the postnatal world. This predictive adaptive response model [158] or weather forecasting model [159,160] predicts that under certain conditions, organisms that are stressed in utero may: Have an adaptive advantage when confronted with stress later in development;

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Be penalized with increased disease risk if they are provided with a nurturing or supportive postnatal environment [161] .

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There is persuasive support for the predictive adaptive response model from studies that have examined the consequences of discordance between prenatal and postnatal nutrient environments. For instance, the risk for altered cardiovascular function and cardiac hypertrophy in sheep is increased by manipulating the discrepancy between prenatal and postnatal nutrition [162] , and the risk of developing metabolic future science group

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diseases increases in individuals provided with sufficient nutrition after prenatal exposure to near-starvation [163,164] . Conclusion

Stress undeniably and profoundly influences the developing human fetus, with consequences that persist into childhood and very likely for the entire lifespan. However, it is important to acknowledge the independent and joint influences of psychosocial and biological stress on development. The human placenta integrates numerous sources of maternal stress signals and responds with a dose-dependent release of stress hormones. For example, elevated pCRH concentrations are observed in pregnancies characterized by high levels of maternal stress [165,166] and those complicated by pre-eclampsia, reduced utero–placental perfusion, intrauterine infection and in cases where fetal distress has led to elective preterm delivery [167] . However, because the HPA axis and placental system is responsive to both psychosocial and physiological stress and because these two sources are often independent, the correlation with stress biomarkers is often low. Thus, maternal psychosocial stress does not exclusively determine fetal exposure to biological stress signals and elevated levels of stress hormones do not necessarily reflect the experience of increased maternal stress. The evidence described in this article indicates that both biological and psychosocial sources of stress, especially pregnancy-specific stress, have significant influences on the fetus, with long-term consequences in the infant, child and perhaps beyond. Future perspective

The fetal programming ‘movement’ has had a significant influence on medicine and basic science. In a relatively short time, several international annual meetings have been spawned and a new journal, The Developmental Origins of Health and Disease, has been launched to encourage dissemination of this rapidly expanding area of research. In the USA, the National Children’s Study (NCS) is in the pilot phase, with a goal of assessing the linkage between very early (fetal) exposure in 100,000 individuals to environmental and social stressors and developmental outcomes in early adulthood. It is estimated that the NCS, with about 100 different sites, will cost several billion dollars. Thus, the commitment of the NIH in the USA to this area of science is nearly unprecedented. In advance of the NCS, as www.futuremedicine.com

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illustrated in this article, there are already large prospective studies of fetal exposures around the world that have replaced the important and highly influential initial retrospective reports. These prospective studies are in the early stages and the results are just now entering into the scientific literature. Despite the fact that this area of research is in its embryonic stage, the findings have created a paradigm shift. It is now essential to consider fetal experience (or exposure) in order to fully understand human development. Of course, the sophisticated serial measures of fetal exposures represented in the studies reviewed in this article are not typically available for most adults. However, surrogate retrospective information, such as gestational age at birth and birth weight, are often available, and this information (which is sometimes included in medical reports) may be very helpful for gaining a full appreciation of neurological health. Moreover, many European countries have extensive databases that include a wealth of information about the circumstances surrounding birth, birth outcomes and rich developmental histories. In the future, as the evidence accumulates, more sophisticated assessments of early development will become standard, computerized and available to healthcare professionals. One area of investigation with the potential of making a major advance in improving quality of life is intervention. For major clinical syndromes such as phenylketonuria, Down and others, there are standard tests available to provide information for treatment. In the next 5–10 years, a more comprehensive understanding of the factors influencing ‘normal’ fetal neurological development will emerge. We may come to understand which factors impair and which factors optimize outcomes in the subclinical range. For instance, we reported in this article that normal healthy subjects exposed to different trajectories of naturally occurring cortisol during fetal development have very different intellectual outcomes. One trajectory might predict that a child will have normal but mediocre academic achievement. Another trajectory might predict outstanding academic achievement. The temptation to optimize outcomes by manipulating fetal exposures will be difficult to resist and present ethical challenges. There are already programs to enhance cognition by stimulating the fetus in various ways or by managing maternal stress. As information accumulates, more direct and specific interventions may be become possible. 684


This article has covered the area of gestational stress on cognition, but there are excellent studies on the effects of fetal exposures to stress, anxiety and adversity on pain perception, temperament and social and emotional development. In addition to providing very early markers of cognitive potential, the study of the human fetus may make even more profound advances in understanding the risks for personality and psychiatric disorders. There are several areas of research that must continue to evolve. First, a more comprehensive understanding of the fetal experience is critical. This article focused on stress-related exposures and primarily endocrine markers. However, there is growing interest in vascular and immune exposures that exert both independent and additive influences on fetal health and developmental outcomes. It is important that the field of fetal neurology/psychology explores the mechanisms of communication of stress and adversity between the host (mother) and the fetus. As indicated in this article, the precise mechanisms of communication are largely unknown and in some cases the most plausible candidates have been ruled out. Research in the next 5 years will advance our understanding of the role of the postnatal environment in modulating the influences of prenatal experience. The possibility briefly reviewed here indicates that congruence between prenatal and postnatal exposures may be the most important factor in determining survival and optimal functioning. Finally, in the next 10 years, an understanding should emerge of how and by which mechanisms fetal experience exerts lifelong influences on health and wellbeing. There are several candi dates including the structural changes in the brain described in this article. Epigenetic mechanisms related to conditions of gene expression are among the most promising areas to explore. Acknowledgements

Cheryl Crippen is gratefully acknowledged for her assistance. Financial & competing interests disclosure

Curt A Sandman is supported by the NIH grants NS-41298, HD-51852 and HD‑28413 and Elysia P Davis is supported by the NIH grant HD-50662. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. future science group


Review

Executive summary Programming influences on development The human fetus has evolved mechanisms to acquire information about the environment and guide its development. Early detection of stress signals from the maternal environment (e.g., cortisol) ‘informs’ the fetus that there may be a threat to survival. n Preterm birth is one potential outcome of fetal exposure to stress during gestation. n Aversive intrauterine events imprint a pattern of activity that results in a ‘program’ of disorders with lasting or permanent influences. n The vulnerable fetal brain cannot escape the circulating biochemical fingerprint of maternal stress. n n

Physiology of gestational stress Physiological stress systems change dramatically during pregnancy. The placenta expresses the genes for corticotrophic-releasing hormone (CRH; hCRH mRNA) and the precursor for adrenocorticotropic hormone and b-endorphin. All of these stress hormones increase as pregnancy advances. n By contrast to the negative feedback regulation of hypothalamic CRH, cortisol stimulates the expression of hCRH mRNA in the placenta, establishing a positive feedback loop. n Stressful events early in pregnancy are experienced by the mother as more unpleasant and may exert greater influences on the fetus than events closer to term. n Women become less responsive to stress as gestation advances. n The precise mechanism of communication of stress between the mother and fetus is unknown. n n

Why the effects of gestational stress are sensitive to timing The consequences of stress for the developing fetus are determined by the timetable for fetal organogenesis, vast changes in maternal stress physiology across gestation and changes in placental physiology. n Elevated circulating stress hormones coupled with decreased maternal psychosocial responses to stress as pregnancy advances create a paradoxical situation that might explain why psychological and biological markers of stress during pregnancy exert independent effects on outcome. n

Gestational stress influences the human fetus In humans, the most well-documented effects of exposure to maternal stress are on birth outcomes including preterm delivery. The study of human fetal behavior is important because it provides the opportunity to assess the effects of gestational stress before the effects of external forces are exerted. n Maternal psychosocial stress and biological stress signals affect fetal behavior. n Low levels of maternal CRH at 15 gestational weeks, but not later, predicted a more mature fetal heart rate pattern at 25 gestational weeks. This may be the first uncontaminated evidence of gestational stress exerting programming influences on the nervous system that was completely independent of postnatal experiences. n n

Gestational stress influences infant development Results from animal models have established that fetal exposure to stress is associated with compromised neurodevelopment, enhanced stress reactivity and increased fearful or anxious behavior. n In humans, maternal psychosocial stress is associated with child developmental outcomes. Evidence is emerging that assessment of stress that is specific to pregnancy is a stronger predictor of infant and child neurodevelopmental outcomes than generalized stress. n The trajectory of maternal stress hormones including cortisol shapes the trajectory of fetal development, with consequences for infant temperament and cognitive functioning. The profile of maternal cortisol is more important than levels at a given time point for predicting child outcomes. n

Gestational stress exerts influences on the developing brain during childhood Low birth weight and preterm birth have been related to reductions in regional brain volumes; however, adverse birth outcomes may be markers of in utero stress exposure and the changes in brain morphology may be due to perinatal complications. n Pregnancy-anxiety early in gestation, but not later, was associated with gray matter volume reductions in the prefrontal cortex, the premotor cortex, the medial temporal lobe, the lateral temporal cortex and the postcentral gyrus, as well as the cerebellum extending to the middle occipital gyrus and the fusiform gyrus. n

Mechanisms of stress effects on the developing nervous system The evidence is clear that areas critical for learning, including the hippocampus, are influenced by exposure to prenatal stress and stress hormones. n Exposure to prenatal maternal stress has parallel and direct effects on the fetal brain and on fetal endocrine systems. n Considerable evidence indicates that glucocorticoids, such as cortisol, are neurotoxic to hippocampal CA3 pyramidal cells, and fetal exposure to high levels of glucocorticoids produces irreversible damage to the hippocampus. n Exogenously administered CRH increases neuronal excitation, leading to seizures in limbic areas associated with learning and memory and thismay participate in mechanisms of neuronal injury. n There is reasonable evidence to warrant the conclusion that maternal stress is translated into direct effects on the fetal nervous system. n



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Executive summary Sex-specific programming effects Animal models provide strong evidence for sexually dimorphic responses to stress and adversity. Neurological maturation appears to be more rapid in human female fetuses. n Males appear to be more vulnerable to developmental insults. n n

Conclusion Stress undeniably and profoundly influences the developing human fetus, with consequences that persist into childhood and very likely for the entire lifespan. n It is important to acknowledge the independent and joint influences of psychosocial and biological stress on development. n Both biological and psychosocial sources of stress, especially pregnancy-specific stress, have significant influences on the fetus, with long-term consequences in the infant, child and perhaps beyond. n

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