Elsevier

Psychoneuroendocrinology

Volume 30, Issue 8, September 2005, Pages 724-743
Psychoneuroendocrinology

Psychoneuroendocrine processes in human pregnancy influence fetal development and health

https://doi.org/10.1016/j.psyneuen.2005.02.004Get rights and content

Summary

Individual differences in psychoneuroendocrine function play an important role in health and disease. Developmental models postulate that these individual differences evolve through a progressive series of dynamic time-, place- and context-dependent interactions between genes and environments in fetal, infant and adult life. The effects of early experience have longer-lasting and more permanent consequences than those later in life. Experimental studies in animals have provided convincing evidence to support a causal role for stress-related psychoneuroendocrine processes in negatively influencing critical developmental and health outcomes over the life span, and have also offered valuable insights into putative physiological mechanisms. However, the generalizability of these findings from animals to humans may be limited by the existence of large inter-species differences in physiology and the developmental time-line. We have initiated a program of research in behavioral perinatology and conducted studies over the past several years to examine the effects of stress-related psychoneuroendocrine processes in human pregnancy on fetal developmental and health outcomes. Our findings support a significant and independent role for maternal prenatal stress in the etiology of prematurity-related outcomes, and suggest that these effects are mediated, in part, by the maternal–placental–fetal neuroendocrine axis, and specifically by placental corticotropin-releasing hormone. Our findings also suggest that the use of a fetal challenge paradigm offers a novel way to quantify fetal neurobehavioral maturity in utero, and that the maternal environment exerts a significant influence on the fetal neurodevelopmental processes related to recognition, memory and habituation. Finally, our findings provide preliminary evidence to support the notion that the influence of prenatal stress and maternal–placental hormones on the developing fetus may persist after birth, as assessed by measures of temperament and behavioral reactivity in the first few years of postnatal life. A description of this body of work is followed by the elucidation of questions for further research and a discussion of implications for life-span development and health.

Introduction

The role of individual differences in psychoneurobiological processes in health and diseases of the nervous, endocrine, immune, cardiovascular, reproductive, gastrointestinal and musculoskeletal systems is well established (McEwen, 1998, Sapolsky et al., 2000, Lupien and Lepage, 2001). Research questions in this area can be differentiated into two broad categories: (1) how do such individual differences produce adverse health outcomes, and (2) what are the causes, or determinants, of these individual differences? With respect to the latter question, regarding the origins of individual differences, two kinds of models have guided theory and research. The first category of models emphasize the role of accumulation of adverse social and psychological conditions in producing dysregulation of normally-functioning neurobiological processes (i.e. a cumulative exposure model). The second category of models emphasize the developmental origins of individual differences (i.e. a developmental trajectories model). According to these developmental models, individual differences in psychoneurobiological processes evolve through a series of interactions, or conditional probabilities. The effects of genes (inherited at conception) on fetal developmental and birth outcomes are conditioned by the environment within the fetus and uterus; the effects of fetal outcomes, such as growth and other birth phenotypes, on infant developmental and health outcomes are conditioned by the environment during childhood; and the effects of childhood factors on adult health outcomes are conditioned by lifestyle and other environments in adult life. Any one influence, such as socioeconomic disadvantage, does not have a single quantifiable risk associated with it. Its risk is conditioned by events and environments at earlier, crucial stages of development (i.e. the notion of developmental switches; Barker, 2002).

A parallel theme has evolved in recent years in the developmental neurosciences. Over the last two decades or so there has been a major paradigm shift in developmental biology regarding fundamental concepts of how the central nervous system and the rest of the organism develops and functions. Genes and environment are no longer considered to exert separate influences. Development is viewed not as a gradual elaboration of an architectural plan pre-configured in the genes, but rather as a dynamic interdependency of genes and environment, characterized by a continuous process of interactions in a place- and time-specific dependent manner. These interactions involve short- and long-term information storage, whereby genetic and epigenetic processes, at every step of development, become represented in the evolving structural and functional design of the organism (Institute of Medicine, 1992, Smotherman and Robinson, 1995).

The two key features of these developmental models are, first, that events at one point in time have consequences that are manifested later in the developmental process, and second, that afferent activity has a profound influence on the developmental trajectory (Kolb, 1995). In other words, it appears that within the constraints imposed by the heritable germ line at conception, each developing organism plays an active role in its own construction. This dynamic process is effected by evolving various systems during embryonic and fetal life to acquire information about the nature of the environment, and to use this information to guide development. In the context of this formulation, environment plays a necessary role for development to occur. The degree of congruence or discongruence between fetal, childhood and adult environments determines trajectories leading to either optimal or suboptimal developmental and health outcomes (Bornstein, 1989, Gluckman and Hanson, 2004, Wadhwa et al., 2002a).

Guided by the above framework of development and health, we have conducted studies over the past several years of the effects of psychoneuroendocrine processes in human pregnancy on outcomes related to fetal/infant health and well-being. We have broadly defined this field—behavioral perinatology—as an inter-disciplinary area of research that involves conceptualization of theoretical models and conduct of empirical studies of the dynamic time-, place-, and context-dependent interplay between biological and behavioral processes in fetal, neonatal and infant life. The biobehavioral processes of particular interest to our research group relate to the effects of maternal pre- and perinatal stress and maternal–placental–fetal stress physiology. Our choice of stress and stress physiology is guided by two major considerations: First, empirical studies in humans and animals support a significant role for pre- and perinatal stress as an independent risk factor for adverse developmental and health outcomes (Wadhwa, 1998a). Second, stress and stress physiology offer an excellent model system for the study of early developmental processes because it appears that the developing fetus may acquire and incorporate information about the nature of its environment by using the same systems that mediate subsequent adaptation and central and peripheral responses to challenge/stress (Chrousos, 1998, Chrousos and Gold, 1992, Wadhwa et al., 2002a).

We propose that behavioral perinatology research may have important implications for a better understanding of individual differences in psychoneuroendocrine processes that underlie or contribute to the risk of at least three sets of outcomes: prematurity, adverse neurodevelopment, and chronic degenerative diseases in adulthood. Each of these classes of adverse health outcomes represent major public health issues in the United States and other developed nations, their prevalence is characterized by substantial disparities along factors associated with sociodemographic disadvantage and racial/ethnic minority status (which we and others have argued may, in part, reflect the effects of variations in stress and stress physiology in affected populations), and growing evidence supports a crucial role for early developmental process in their origins (Barker, 1998, Gluckman and Hanson, 2004, Mattison et al., 2001, Nathanielsz, 1999, Wadhwa et al., 2001b, Wadhwa et al., 2001c).

Experimental studies in animals provide convincing evidence to support a causal role for prenatal stress in negatively influencing critical developmental and health outcomes over the life span, including brain structure and function, sexual differentiation, (re)activity of the autonomic nervous, neuroendocrine, immune and reproductive systems, and physical health (for recent reviews see Kofman, 2002, Wadhwa, 1998, Weinstock, 2001a, Weinstock, 2001b). For example, with specific reference to psychoneuroendocrine processes, the application of prenatal stress in rodents has been found to alter baseline and stress-induced responsivity of the hypothalamic–pituitary–adrenal (HPA) axis and levels and distribution of regulatory neurotransmitters, including norepinephrine, dopamine, serotonin and acetyl choline, and to modify key limbic structures. These prenatal stress-induced alterations have been shown to affect cognition (decreased learning), emotionality (increased anxiety) and social behavior (increased withdrawal; Kofman, 2002). Similarly, the application of prenatal stress in non-human primates has been shown to alter endocrine, immune and neurobehavioral outcomes in offspring (Coe and Lubach, 2000, Schneider et al., 2001). Such animal studies have also offered valuable insights into putative physiological mechanisms that may be involved in mediating the effects of stressful maternal and intrauterine environments on the developing organism. However, the generalizability of some of these findings from animals to humans may be limited by the existence of inter-species differences in physiology and the developmental time-line. Perhaps no single system exemplifies the magnitude of these inter-species physiological differences as vividly as the reproductive system, even between otherwise very closely related species such as humans and non-human primates (Smith, 1999, Smith, 2001). For example, primates are the only species that produce placental corticotropin-releasing hormone (CRH) during pregnancy. The timing of maturation of the HPA axis relative to birth is also highly species-specific and is closely linked to landmarks of brain development (Dobbing and Sands, 1979). In animals that give birth to precocious offspring (sheep, guinea pigs, primates), maximal brain growth and a large proportion of neuroendocrine maturation takes place in utero. By contrast, in species that give birth to non-precocious offspring (rats, rabbits, mice), much of neuroendocrine development occurs in the postnatal period (Dent et al., 2000).

Based on the above considerations, four sets of issues have guided our work in humans on psychoneuroendocrine influences in pregnancy and fetal/infant development, namely those related to (1) outcome-specificity, (2) stressor-specificity, (3) critical periods of vulnerability, and (4) mediating mechanisms. We have articulated a neurobiological model of prenatal stress, that proposes maternal psychosocial stress exerts a significant and independent negative influence on fetal developmental outcomes. We suggest that these effects are mediated, in part, via maternal–placental–fetal neuroendocrine mechanisms, with a central role for placental CRH. Based on our understanding of the ontogeny of fetal development, the endocrinology of human pregnancy, and heterogeneity of pathophysiological mechanisms leading to adverse outcomes, our model further hypothesizes that the effects of prenatal stress are outcome-specific, and that they are moderated by the nature, timing and duration of stress (Wadhwa, 1998, Wadhwa et al., 2001b, Wadhwa et al., 2002a), (Fig. 1).

We specifically postulate that individual differences in maternal stress appraisals exert a larger impact than exposure per se to stressful events; that prenatal stress in early gestation exerts a larger impact on outcomes related to the length of gestation and fetal growth than stress in the latter part of gestation; that among spontaneous births (i.e. those following spontaneous labor or rupture of fetal membranes) prenatal stress directly influences the length of gestation, whereas among elective births, prenatal stress indirectly influences the length of gestation by contributing to increased risk of obstetric complications (e.g. preeclampsia) that are indicators for elective delivery; and that the maternal–placental–fetal neuroendocrine system is the primary physiological mediator of the effects of prenatal stress on adverse fetal outcomes because it constitutes the most fundamental and basic substrate for fetal growth, development and parturition, and because pathways through which alterations in other systems (e.g. immune, vascular) produce pathophysiological consequences are mediated, in part, by maternal–placental–fetal neuroendocrine processes.

Section snippets

Research methods: an overview

We have tested components of our psychoneurobiological model of prenatal stress in a series of prospective, longitudinal, population-based cohort studies in women with singleton, intrauterine pregnancies, recruited during the late first or second trimester of gestation and followed through delivery into the postpartum period. Our recruitment strategy has ensured heterogeneity in terms socio-demographic and racial/ethnic characteristics, and based on conventional measures of obstetric risk we

Maternal psychosocial processes and infant birth outcomes

The belief that a mother's emotional state during pregnancy may influence the development of her fetus has existed since ancient times across all cultures. Research studies examining the effects of prenatal stress first appeared in the literature in the mid 1950s. Much of the earlier work in this area was, however, limited by conceptual and methodological problems, including inadequate conceptualization and operationalization of predictor as well as outcome variables, retrospective methodology,

Discussion and future directions

In summary, our above-described findings (a) support a significant and independent role for maternal psychosocial processes such as high prenatal stress or low social support in the etiology of prematurity-related outcomes; (b) suggest that these effects are mediated, in part, by the maternal–placental–fetal neuroendocrine axis; (c) raise the possibility that the observed racial/ethnic disparities in reproductive health outcomes may be related, in part, to differences in

Acknowledgements

This Customer work was supported, in part, by US PHS (NIH) grants HD–33506, HD–41696, HD–47609, HD–28413, HD–40967 and NS-41298.

References (127)

  • I.J. Elenkov et al.

    Stress hormones Th1/Th2 patterns, pro/anti-inflammatory cytokines and susceptibility to disease

    Trends Endocrinol. Metab.

    (1999)
  • L. Glynn et al.

    When stress happens matters: the effects of earthquake timing on stress responsivity in pregnancy

    Am. J. Obstet. Gynecol.

    (2001)
  • L.M. Glynn et al.

    Pregnancy affects the appraisal of negative life events

    J. Psychosom. Res.

    (2004)
  • V.K. Han et al.

    Spatial and temporal patterns of expression of messenger RNA for insulin-like growth factors and their binding proteins in the placenta of man and laboratory animals

    Placenta

    (2000)
  • C.J. Hobel et al.

    Maternal plasma corticotropin-releasing hormone associated with stress at 20 weeks gestation in pregnancies ending in preterm delivery

    Am. J. Obstet. Gynecol.

    (1999)
  • C. Holzman et al.

    Second trimester corticotropin-releasing hormone levels in relation to preterm delivery and ethnicity

    Obstet. Gynecol.

    (2001)
  • O. Kofman

    The role of prenatal stress in the etiology of developmental behavioural disorders

    Neurosci. Biobehav. Rev.

    (2002)
  • S.J. Lupien et al.

    Stress, memory, and the hippocampus: can't live with it, can't live without it

    Behav. Brain Res.

    (2001)
  • S.G. Matthews

    Early programming of the hypothalamo–pituitary–adrenal axis

    Trends Endocrinol. Metab.

    (2002)
  • B.S. McEwen et al.

    The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions

    Brain Res. Rev.

    (1997)
  • H. Nisell et al.

    Sympathoadrenal and cardiovascular reactivity in pregnancy-induced hypertension-II. Responses to tilting

    Am. J. Obstet. Gynecol.

    (1985)
  • T.G. O'Connor et al.

    Antenatal anxiety predicts child behavioral/emotional problems independently of postnatal depression

    J. Am. Acad. Child Adolesc. Psychiatry

    (2002)
  • S.E. Ozanne et al.

    Early programming of glucose-insulin metabolism

    Trends Endocrinol. Metab.

    (2002)
  • K.M. Paarlberg et al.

    Psychosocial factors and pregnancy outcome: a review with emphasis on methodological issues

    J. Psychosom. Res.

    (1995)
  • F. Petraglia et al.

    Neurotransmitters and peptides modulate the release of immunoreactive corticotropin-releasing factor from cultured human placental cells

    Am. J. Obstet. Gynecol.

    (1989)
  • C.W. Pritchard et al.

    Preterm birth, low birthweight and the stressfulness of the household role for pregnant women

    Social Sci. Med.

    (1994)
  • J.R. Seckl

    Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms

    Mol. Cell Endocrinol.

    (2001)
  • M.M. Slattery et al.

    Preterm delivery

    Lancet

    (2002)
  • J. Axelrod et al.

    Stress hormones: their interaction and regulation

    Science

    (1984)
  • D.J.P. Barker

    Mothers, babies and health in later

    (1998)
  • M.H. Bornstein

    Sensitive periods in development: structural characteristics and causal interpretations

    Psychol. Bull.

    (1989)
  • H. Cabral et al.

    Foreign-born and US-born black women: differences in health behaviors and birth outcomes

    Am. J. Public Health

    (1990)
  • F. Cambien et al.

    Angiotensin, I-converting enzyme gene polymorphism modulates the consequences of in utero growth retardation on plasma insulin in young adults

    Diabetes

    (1998)
  • J.R.G. Challis et al.

    Endocrine and paracrine regulation of birth at term, and preterm

    Endocrine Rev.

    (2000)
  • G.P. Chrousos

    Stressors, stress, and neuroendocrine integration of the adaptive response

    Ann. NY Acad. Sci.

    (1998)
  • G.P. Chrousos et al.

    The concepts and stress and stress systems disorders

    JAMA

    (1992)
  • C.L. Coe et al.

    Prenatal influences on neuroimmune set points in infancy

    Ann. NY Acad. Sci.

    (2000)
  • S. Cohen et al.

    Psychological stress and susceptibility to the common cold

    N. Engl. J. Med.

    (1991)
  • S. Cohen et al.

    Psychological stress, cytokine production, and severity of upper respiratory illness

    Psychosom. Med.

    (1999)
  • J. Collins et al.

    Relation of maternal race to the risk of preterm non-low birthweight infants: a population study

    Am. J. Epidemiol.

    (1996)
  • M. Constancia

    Placental-specific IGF-II is a major modulator of placental and fetal growth

    Nature

    (2002)
  • J.D. Coplan et al.

    Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early life stressors: implications for the pathophysiology of mood and anxiety disorders

    Proc. Natl Acad. Sci. USA

    (1996)
  • J.F. Culhane et al.

    Maternal stress is associated with bacterial vaginosis in human pregnancy

    Matern. Child Health J.

    (2001)
  • G.W. Dent et al.

    Rapid induction of corticotropin-releasing hormone gene transcription in the paraventricular nucleus of the developing rat

    Endocrinology

    (2000)
  • J.A. DiPietro et al.

    Fetal neurobehavioral development

    Child Dev.

    (1996)
  • J.A. Di Pietro et al.

    Antenatal origins of individual differences in heart rate

    Dev. Psychobiol.

    (2000)
  • J.A. Di Pietro et al.

    What does fetal movement predict about behavior during the first two years of life?

    Dev. Psychobiol.

    (2002)
  • J.A. Di Pietro et al.

    Maternal stress and affect influence fetal neurobehavioral development

    Dev. Psychol.

    (2002)
  • N. Dole et al.

    Maternal stress and preterm birth

    Am. J. Epidemiol.

    (2003)
  • K. Erickson et al.

    Preterm birth: associated neuroendocrine, medical, and behavioral risk factors

    J. Clin. Endocrinol. Metab.

    (2001)
  • Cited by (316)

    • Role of placenta in developmental programming of sex-specific adult outcomes

      2022, Perinatal and Developmental Epigenetics: Volume 32 in Translational Epigenetics
    • Effects of stress on reproductive function and fetal development

      2022, Reproductive and Developmental Toxicology
    • Evaluation of maternal inflammation as a marker of future offspring ADHD symptoms: A prospective investigation

      2020, Brain, Behavior, and Immunity
      Citation Excerpt :

      Biologically, several mechanisms may account for this association: maternal cytokines (a) can cross the placenta, resulting in elevated cytokine concentrations in amniotic fluid and in the fetal brain (Urakubo et al., 2001; Zaretsky et al., 2004); (b) can induce epigenetic changes in the placenta in ways that increase placental cytokine expression (Hsiao and Patterson, 2011; Urakubo et al., 2001); (c) can activate resident immune cells in the decidua, thereby prompting cytokine release at the maternal-fetal interface; and (d) increased cytokines in the intrauterine milieu can prompt a fetal inflammatory response, which can further contribute to the inflammatory profile of the fetal brain (Schaafsma et al., 2017). Increased cytokines in the intrauterine environment and fetal brain can shape or perturb brain development in ways that alter behavior early in life (Bilbo and Schwarz, 2009; Wadhwa, 2005). Although of secondary emphasis, our finding that cytokine levels mediated effects of maternal risk factors is, while preliminary, also novel and of interest to theories examining mechanisms of those risks.

    View all citing articles on Scopus
    View full text