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

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Abstract

Substantial evidence from preclinical laboratory studies indicates that prenatal stress (PS) affects the hormonal and behavioural development of offspring. In the following review, the effects of PS in rodents and non-human primates on hypothalamic–pituitary–adrenal (HPA) reactivity to stress, morphological changes in the brain, motor behaviour and learning are surveyed. PS has been found to alter baseline and stress-induced responsivity of the HPA axis and levels and distribution of regulatory neurotransmitters, such as norepinepherine, dopamine, serotonin and acetylcholine and to modify key limbic structures. In rodents and non-human primates, PS affected learning, anxiety and social behaviour. The relevance of these findings to humans is discussed with respect to (a) the effect of administration of exogenous corticosteroids in pregnancy and (b) maternal state and trait anxiety during gestation and its relation to foetal autonomic regulation as putative predisposing factors in the pathogenesis of behavioural developmental delays in children.

Section snippets

Stress response

Animals react to stress by mobilizing energy stores in preparation for a brief surge of enhanced activity (‘flight or fight’). The stress response is mediated by a sequence of neurological and endocrine messages involving the secretion of corticotropin releasing factor (CRF) and arginine vasopressin (AVP) by the paraventricular nucleus (PVN) of the hypothalamus, which in turn stimulate the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary lobe. ACTH stimulates release of

Hormonal responses to prenatal stress throughout the life span

A range of stressors has been used in rodent studies of PS. Mild to moderate stressors include exposing the pregnant dam to saline injections, or unpredictable noise, whereas more severe stress entails daily restraint stress, cold water immersion, or electric shock to the tail. The time-course of the hormonal sequelae of PS has not been fully elucidated. CORT and ACTH were elevated in the hypothalami of foetuses of both sexes following treatment of the pregnant dam with either restraint stress

PS-induced structural modification of limbic structures in brain

Limbic structures involved in regulation of the stress response are particularly vulnerable to stress in adults, as evidenced by the reduction in hippocampal volume in patients with post-traumatic stress disorder (PTSD) [14] and in monkeys who had been exposed to severe social stress and drastic weight loss [123]. Although changes in hippocampal volume in primates following PS have not been reported, Uno et al. [122] reported that prenatal administration of dexamethasone to pregnant rhesus

Effect of PS on behavioural measures

Several developmental measures have been studied in relation to PS, including motor development, body weight and developmental milestones, immune system, cardiovascular health, sexual development and behaviour [20], [131]; however, this review will focus only on some aspects of locomotion, learning, and reactivity to stress in PS offspring.

Mediation of PS effects by maternal CORT

There is substantial evidence that endogenous GCs mediate some of the changes in HPA responsiveness in PS offspring both in rodents and primates [69]. Administration of exogenous GCs to the pregnant dam mimics the effects of PS and conversely, adrenalectomy (ADX) counteracts the effects of PS.

Foetuses are protected to some extent from circulating maternal GCs by placental 11β-HSD type 2 [69], [133]. This enzyme has less activity for synthetic than for endogenous GCs, which may account for the

PS in non-human primates: effects on hormonal response, neurotransmitters and behaviour

Primate brain development differs from that of rodents in that much of the neuroendocrine maturation occurs in utero [69]. This suggests that the time course for the effects of PS on development may be different. Thus, it is critical to demonstrate that the behavioural effects of PS can be demonstrated in primate species. The studies of PS in several primate species suggest that social and emotional stressors can affect the behavioural and motor development of offspring. Because the stressed

Developmental sequelae to steroid administration in pregnancy

One approach to this issue has been to examine the effects of exogenous steroids on birth outcome and later development. Since synthetic corticoids, such as dexamethasone, are not easily metabolized and may cross the placental barrier more readily than cortisol [133], they are liable to affect intellectual and social development. Exogenous steroids are routinely administered to pregnant women whose foetuses are diagnosed with congenital adrenal hyperplasia (CAH) or to women who are expected to

Acknowledgements

The author thanks the anonymous referee for helpful comments on the manuscript.

References (135)

  • E. Fride et al.

    Increased interhemispheric coupling of the dopamine systems induced by prenatal stress

    Brain Res Bull

    (1987)
  • T. Fujioka et al.

    Mild prenatal stress enhances learning performance in the non-adopted rat offspring

    Neuroscience

    (2001)
  • C. Henry et al.

    Prenatal stress in rats facilitates amphetamine-induced sensitization and induces long-lasting changes in dopamine receptors in the nucleus accumbens

    Brain Res

    (1995)
  • H.E. Jones et al.

    Prenatal stress alters the size of the rostral anterior commissure in rats

    Brain Res Bull

    (1997)
  • R. Joseph

    Fetal brain behavior and cognitive development

    Develop Rev

    (2000)
  • S. Kaiser et al.

    Social stress during pregnancy and lactation affects in guinea pigs the male offsprings' endocrine status and infantilizes their behavior

    Psychoneuroendocrinology

    (2001)
  • B.S. Kisilevsky et al.

    Human fetal behavior: 100 years of study

    Develop Rev

    (1998)
  • M. Koehl et al.

    Nicotine-induced locomotor activity is increased by preexposure of rats to prenatal stress

    Brain Res

    (2000)
  • J. Lehmann et al.

    Long-term effects of prenatal stress experience and postnatal maternal separation on emotionality and attentional processes

    Behav Brain Res

    (2000)
  • E.D. Lephart et al.

    Calbindin-D28K is regulated by adrenal steroids in the hypothalamic tissue during prenatal development

    Dev Brain Res

    (1997)
  • C.M. McCormick et al.

    Sex-specific effects of prenatal stress on hypothalamic–pituitary–adrenal responses to stress and brain glucocorticoid receptor density in adult rats

    Dev Brain Res

    (1995)
  • S. Milberger et al.

    Pregnancy, delivery and infancy complications and attention deficit hyperactivity disorder: issues of gene–environment interaction

    Biol Psychiat

    (1997)
  • H. Nishio et al.

    Prenatal stress and postnatal development of neonatal rats—sex-dependent effects on emotional behavior and learning ability of neonatal rats

    Int J Dev Neurosci

    (2001)
  • R. Paludetto et al.

    Maternal dysphoria and postnatal environmental stress adaptation

    Lancet

    (2000)
  • M.C. Pardon et al.

    Influence of prepartum chronic ultramild stress on maternal pup care behavior in mice

    Biol Psychiat

    (2000)
  • D.A.V. Peters

    Maternal stress increases fetal brain and neonatal cerebral cortex 5-hydroxytryptamine synthesis in rats: a possible mechanism by which stress influences brain development

    Pharmacol Biochem Behav

    (1990)
  • D.A.V. Peters

    Prenatal stress: effects on brain biogenic amine and plasma corticosterone levels

    Pharmacol Biochem Behav

    (1982)
  • D.A.V. Peters

    Effects of maternal stress during different gestational periods on the serotonergic system in adult rat offspring

    Pharmacol Biochem Behav

    (1988)
  • R.M. Sapolsky et al.

    Maturation of the adrenocortical stress response: neuroendocrine control mechanisms and the stress hyporesponsive period

    Brain Res Rev

    (1986)
  • M.L. Schneider

    The effect of mild stress during pregnancy on birthweight and neuromotor maturation in rhesus monkey infants (Macaca mulatta)

    Infant Behav Dev

    (1992)
  • Collaborative possibilities for molecular genetic studies of attention deficit hyperactivity disorder. Report from an international conference

    Am J Med Genet (Neuropsychiat Genet)

    (2000)
  • L.S. Allen et al.

    Sexual dimorphism of the human anterior commissure

    Anat Rec

    (1986)
  • L.S. Allen et al.

    Two sexually dimorphic cell groups in the human brain

    J Neurosci

    (1989)
  • A. Arnsten

    Development of the cerebral cortex: XIV. Stress impairs prefrontal cortical function

    J Am Acad Child Adolesc Psychiatry

    (1999)
  • J. Auerbach et al.

    Dopamine D4 receptor (D4DR) and serotonin transporter promoter (5-HTTLPR) polymorphisms in the determination of temperament in 2-month-old infants

    Mol Psychiat

    (1999)
  • E.H. Aylward et al.

    Basal ganglia volumes in children with attention-deficit hyperactivity disorder

    J Child Neurol

    (1996)
  • A. Barbazanges et al.

    Maternal glucocorticoid secretion mediates long-term effects of prenatal stress

    J Neurosci

    (1996)
  • R.A. Barkley et al.

    Frontal lobe functions in attention deficit disorder with and without hyperactivity: a review and research report

    J Ab Child Psychol

    (1992)
  • A. Bechara et al.

    Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans

    Science

    (1995)
  • D.F. Benson

    The role of frontal dysfunction in attention deficit hyperactivity disorder

    J Child Neurol

    (1991)
  • C.W. Berridge et al.

    Engagement in a non-escape (displacement) behavior elicits a selective and lateralized suppression of frontal cortical dopaminergic utilization in stress

    Synapse

    (1999)
  • J. Biederman et al.

    Family–environment risk factors for attention-deficit hyperactivity disorder. A test of Rutter's indicators of adversity

    Arch Gen Psychiatry

    (1995)
  • J.D. Bremner et al.

    MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder

    Am J Psychiatry

    (1995)
  • A.S. Brown et al.

    Further evidence of relation between prenatal famine and major effective disorder

    Am J Psychiatry

    (2000)
  • F.X. Castellanos

    Toward a pathophysiology of attention deficit/hyperactive disorder

    Clin Pediatr (Phila)

    (1997)
  • F.X. Castellanos et al.

    Quantitative morphology of the caudate nucleus in attention deficit hyperactive disorder

    Am J Psychiatry

    (1994)
  • F.X. Castellanos et al.

    Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder

    Arch Gen Psychiatry

    (1996)
  • P.M. Clark

    Programming of the hypothalamic–pituitary–adrenal axis and the fetal origins of adult disease hypothesis

    Eur J Pediatr

    (1998)
  • A.S. Clarke et al.

    Effects of prenatal stress on behavior in adolescent rhesus monkeys

    Ann NY Acad Sci

    (1997)
  • A.S. Clarke et al.

    Long-term effects of prenatal stress on HPA axis in juvenile rhesus monkeys

    Dev Psychobiol

    (1994)
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