Alterations induced by gestational stress in brain morphology and behaviour of the offspring
Introduction
In recent years, there has been increasing awareness that various forms of pathological behaviour in humans may be the outcome of an interaction between genetic factors and the prenatal and postnatal environments. The early observations of Sontag (1941) of a relationship between adverse events creating an emotional disturbance in the pregnant mother and to feeding difficulties in the infants stimulated many studies on the possible effects of gestational stress on infant development and behaviour. Some authors reported an association between maternal psychological stress and birth weight, physical development (Jones and Tauscher, 1978, Knipschild et al., 1981, Lou et al., 1994), a higher incidence of emotional disturbance in their infants (Stott, 1973, Meijer, 1985, Ward, 1991) and hyperactivity-attention deficit disorder (Clements, 1992). An association was also described between maternal stress and an increased likelihood of Gilles de la Tourette's syndrome (TS) (Pasamanick and Kawi, 1956), schizophrenia and depressive symptomatology (Huttunen and Niskanen, 1978, Van Os and Selten, 1998, Watson et al., 1999) in prenatally stressed (PS) offspring. However, others failed to find any relationship between maternal stress and infant development or early or adult behaviour (Minde et al., 1968, Brooke et al., 1989, Selten et al., 1999). The inconsistencies in the earlier studies and difficulties in their interpretation may stem from methodological weaknesses. These include failure to account for genetic factors, parity, concomitant illness, smoking, alcohol or drug intake, timing of stress exposure and whether the stress was a single episode or recurrent. There may also be bias in retrospective reporting of gestational events by mothers of children with behavioural abnormalities. Furthermore, little attention has been devoted to defining psychological stress, to developing appropriate ways to measure it, or to account for individual differences in coping with it. The methodological shortcomings of these earlier studies are described in detail in a review by Lobel (1994).
Low birth weight and preterm delivery are major determinants of infant morbidity (Newton and Hunt, 1984, McCormick, 1985, Verloove-Vanhorick et al., 1986, Hakulinen et al., 1988). The latter includes neurological and behavioural aberrations in the surviving infants (Taylor et al., 1985, Holst et al., 1989, Hadders-Algra et al., 1988). More carefully controlled prospective and retrospective studies have been able to show that adverse life events during pregnancy and/or self-reported anxiety are indeed associated with low birth weight (less than 2.5 kg) and/or preterm delivery (before the 37th week) (Mutale et al., 1991, Steer et al., 1992, Hedegaard et al., 1993, Hedegaard et al., 1996, Wadhwa et al., 1993, Zambrana et al., 1999). However, while birth weight and length of gestation can reasonably be related to maternal stress, after other confounding factors have been controlled, such a relationship is much more difficult to show for neurological and behavioural pathology in the offspring for several reasons. First, there may be a strong genetic component in the mediation of these behavioural aberrations (O'Connor et al., 1998, Bierut et al., 1999, Tsuang, 2000). Second, the environmental or social circumstances that engendered the stress in the mother may continue after the birth of the infant and affect its development and behaviour either directly or through rearing by an overanxious mother. Third, abnormal behaviour in infants, children or adults may not be so readily detected under control conditions but only during a mildly stressful event, such as exposure to the novel environment of a school or kindergarten (Meijer, 1985). This was shown to occur in experimental animals (see Sections 5.3 and 5.4). Lastly, pathological behaviour like schizophrenia or depression only becomes manifest some decades after gestation necessitating the acquisition of information about gestational events from medical records, which may be incomplete, or from maternal recollection, which may be influenced by her knowledge of behavioural abnormalities in her child. Environmental and genetic factors are more easily controlled in studies on the effect of gestational stress in experimental animals. However, the range of behavioural abnormalities is much more limited and cannot always be related to those in human subjects. The aim of this review is to evaluate critically the evidence from human and animal studies for a role of prenatal stress in the aetiology of behavioural pathology.
Section snippets
Methods of assessment
Research on the effects of psychological stress or adverse life events during pregnancy on the development and behaviour of the offspring can broadly be classified into two groups. The first are those in which the mother was not interviewed, but it was presumed that she was under severe psychological stress because she experienced adverse life events or more serious emotional trauma. These include natural disasters, such as floods (Selten et al., 1999) or earthquakes (Watson et al., 1999), or
Comparative brain development in foetal rats and humans
The majority of experiments on the effects of gestational stress on development and behaviour in the offspring have been carried out in rats, because sufficient numbers can be included in each study to obtain statistically significant differences between experimental and control groups. There are also a few studies in Rhesus and squirrel monkeys that largely support the direction of the findings in rats. (Schneider, 1992, Clarke and Schneider, 1993). Any attempt to extrapolate from data on the
Effect of gestational stress on the hypothalamic–pituitary–adrenal axis
Activation of the HPA axis in response to psychological stress in the pregnant female could play an important role in the regulation of the stress response in the offspring in later life and may be responsible for some of their behavioural pathology.
Methodological considerations
Studies on the effects of gestational stress in experimental animals have the advantage that one can more easily control for potential genetic differences, the timing and intensity of the stress, and the postnatal environment than in human subjects. However, they still do not enable us to assess accurately the degree of fear or anxiety engendered by the stress in the mother and her physiological and emotional response to it. This also has a genetic component since it varies considerably in
Conclusions
The data from human subjects and experimental animals suggest that chronic gestational stress can have long-term effects on neuronal development. This may induce different types of behavioural pathology that can be detected in infancy and persist into adulthood. The nature of the behavioural abnormalities are probably determined by the time of occurrence of the maternal stress in relation to the stage of development of particular neuronal systems. The putative mechanisms involve an interaction
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Leon & Mina Deutsch Professor of Psychopharmacology.