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Neuroscience and Biobehavioral Reviews 26 (2002) 457470


The role of prenatal stress in the etiology of

developmental behavioural disorders
Ora Kofman*
Department of Behavioural Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, P.O. Box 653, 84105 Beersheva, Israel
Received 25 September 2001; revised 22 April 2002; accepted 22 April 2002

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. q 2002 Elsevier Science Ltd. All rights
Keywords: Prenatal stress; Hypothalamic pituitaryadrenal axis; Corticosteroids; Locomotion; Emotional reactivity; Learning; Foetal heart rate variability;
Attention deficits

1. Stress response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Biochemical effects of in utero stress in laboratory rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Hormonal responses to prenatal stress throughout the life span . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Sex differences in the hormonal response to prenatal stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3. Effects of PS on modulatory neurotransmitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4. Changes in motor lateralization and dopamine asymmetry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. PS-induced structural modification of limbic structures in brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Effect of PS on behavioural measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Motor development and locomotion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Behavioural reactivity to aversive stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4. Courtship and maternal behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Mediation of PS effects by maternal CORT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. PS in non-human primates: effects on hormonal response, neurotransmitters and behaviour. . . . . . . . . . . . . . . . . . .
7. How relevant are prenatal stress studies in laboratory animals to human development? . . . . . . . . . . . . . . . . . . . . . .
7.1. Developmental sequelae to steroid administration in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2. Developmental sequelae to prenatal stress in infants and children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3. Foetal heart rate and movement as indices of central nervous system control . . . . . . . . . . . . . . . . . . . . . . . . .
7.4. Foetal behavioural response to maternal anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

* Tel.: 972-8-647-2032; fax: 972-8-647-2932.

E-mail address: (O. Kofman).
0149-7634/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
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O. Kofman / Neuroscience and Biobehavioral Reviews 26 (2002) 457470

In the last two decades increasing attention has been

focussed on the contribution of environmental stressors
to behavioural developmental disorders. The most
dramatic of these studies is the series of reports linking
pregnancy during the Dutch hungerwinter of 1944
1995 to a higher incidence of schizophrenia [116] and
affective disorder [15]. Prewar psychological stress was
cited as a contributing factor to the higher incidence of
behavioural problems and developmental delays in
Israeli boys whose mothers who were pregnant during
the stressful period preceding and during the 6-Day War
in 1967 [76] compared to children born 2 years later.
Paternal death was associated with a higher incidence of
schizophrenia in the widows sons, if the tragedy
occurred during gestation, but not postnatally [47].
More prevalent personal tragedies, such as marital strife
or low socio-economic status in pregnancy have also been
found to be associated with developmental delays or
attention deficits in childhood [13,78,115]. Many variables,
such as malnutrition, susceptibility to disease, delivery
complications and drug use during pregnancy [37,78,113]
can contribute to the effects of stress on foetal development.
However, Huttenen et al. [47] found that birth complications
were actually more prevalent in the control (postnatal
paternal loss) group than in the women who were widowed
during their pregnancy. Thus, birth complications do not
necessarily mediate the subsequent pathology. Another
confounding factor is that many of the environmental
stressors cited, such as low socio-economic status, marital
and family strife, and paternal criminality persist after
pregnancy, thereby influencing development well into
In the following review, evidence for prenatal stress (PS)
as a predisposing factor in the developmental delay of
learning and emotional regulation will be surveyed from
studies involving laboratory rodents and non-human
primates. There is compelling evidence that stress, or
administration of glucocorticoids (GCs) in pregnancy has
structural, pharmacological and behavioural effects on
offspring of laboratory rodents or non-human primates
[132]. In contrast, there is a dearth of research on the longterm effects of PS on behavioural development beyond
infancy. The implications of the preclinical studies will be
considered in light of research on studies of the effects of
exogenous prenatal GCs or of PS on autonomic nervous
system control and cognitive development in infants and

1. 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 GC and
some mineralocorticoid steroid hormones from the adrenal
glands [74,95]. Corticosteroids enhance catabolic, and
suppress anabolic processes by increasing circulating levels
of energy substratesglucose, free fatty acids and free
amino acids. The major GC in rodents is corticosterone
(CORT), and in humans, cortisol. In addition, the immune
response and processes involving cellular growth and
reproduction are temporarily inhibited, to allow the animal
to utilize resources for action. While short-term activation
of the hypothalamic pituitary adrenal (HPA) axis allows
for rapid mobilization of energy stores, in the long run,
suppression of anabolic processes, depletion of energy
stores and suppression of the immune system can be
devastating to the organism [49,72,95].
In addition to the primary hormonal feedback loops
within the HPA axis [96], the stress response is
regulated by negative feedback from high affinity
mineralocorticoid (MR) and low affinity glucocorticoid
receptors (GR) in the hippocampus [49,51,96] and GRs
in the anterior cingulate cortex [30]. GRs are thought to
be sensitive to stress-induced elevated levels of CORT.
Positive feedback from amygdala GC receptors can
enhance the stress response in fear-conditioned learning
and fear-potentiated startle [58].
The presence of GRs in the rat hippocampus, hypothalamus and pituitary has been shown from gestational day 13
[69]. Evidence from studies in rats suggests that the HPA
axis is functional in the foetus in late pregnancy, suppressed
in early postnatal period, and functional at an adult level by
about 15 days [97]. Notably, most of the hormonal and
behavioural stress effects reported in rodents (reviewed
later) involve stress during the last week (trimester) of
gestation. In sheep and primates, the cortisol response to
pituitary ACTH fluctuates during the course of pregnancy,
with a suppression of the response in mid-gestation [19].
During the latter part of gestation, the negative feedback
from cortisol to pituitary is suppressed. It is thought that
upregulation of circulating cortisol binding globulin (CBG)
which reduces levels of free cortisol, down-regulation of
hypothalamic GRs and increased 11b-hydroxysteroid
hydrogenase (11b-HSD), which metabolizes cortisol, contribute to the suppression of the negative feedback. In
umbilical cord blood samples from healthy foetuses
subsequently born at term, foetal ACTH and cortisol, but
not CRH levels increased with gestational age between 18
and 40 weeks [65]. Thus, while mechanisms exist to protect
the foetus from maternal cortisol, it is likely that overproduction of cortisol following stress could have adverse
effects on the developing foetal HPA axis at different stages
in gestation, and that cortisol could even precipitate
premature delivery and suppress foetal growth [19].

O. Kofman / Neuroscience and Biobehavioral Reviews 26 (2002) 457470

2. Biochemical effects of in utero stress in laboratory

2.1. 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 timecourse 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 [61] or mild
stress induced by saline injections in a novel environment
[108] from gestational days (GD) 14 20. After birth, both
basal and stress-induced levels of stress hormones of PS
offspring were elevated compared to controls. Male PS
offspring had higher basal levels of ACTH and CORT at 14
days [119,120] and elevated CORT at 60 90 days [128]. PS
males also showed greater elevations of ACTH and CORT
than controls in response to a tail shock stressor at ages 7, 14
and 21 days [119,120]. Mild PS also elevated the basal
levels and release of CRF in the amygdala of male offspring,
linking PS effects specifically to a nucleus involved in fearrelated behaviours [23].
The hormonal response to stress in PS male rats may
fluctuate during the life cycle. No elevation in the tail-shock
induced ACTH release was reported in PS male rats aged
70 90 days [119,121], whereas the duration, but not the
amplitude of CORT release after restraint stress, was
enhanced at 90 days [68]. Smythe et al. [110] found reduced
plasma CORT in 4-month old male rats following PS
restraint stress, in contrast to the increase found at younger
ages. Notably, female, but not male PS rats, whose mothers
had been subjected to restraint thrice daily in the last
trimester, had elevated basal and swim-stress induced
CORT levels as late as 12 months of age [118]. Several
studies have also reported reduced binding of hippocampal
GRs [45,57,68,118] in PS rats. Reduction in GRs may
attenuate the negative feedback that inhibits the stress
response in offspring, leading to elevation of CORT and
2.2. Sex differences in the hormonal response to prenatal
There is preliminary evidence that the HPA axis response
to stress is sexually dimorphic [100,118]. Disparate
responses between males and females are observed not
only with respect to basal levels of ACTH and CORT [120],
but more strikingly in the hormonal response of PS offspring
to stress in adulthood. PS females had a higher overall
ACTH response to restraint stress than did female controls,
whereas PS males, showed faster recovery of stress-induced


elevations in ACTH than did non-stressed males [71]. A

phase shift toward peak secretion of CORT and free plasma
CORT in the light cycle was reported in both sexes after PS
[57], but only females had significant elevations of CORT
during all phases of the light/dark cycle. PS reduced the
corticosteroid receptor densities in the cerebral cortex of
males, but increased the receptor density in females [71].
The effect of gonadal hormones on the stress response was
further elaborated by Shanks et al. [104], who reported a
gender-specific response of the HPA axis to injection of a
toxin (Salmonella endotoxin) in rats. Females had higher
CORT levels in response to endotoxin than did males, an
effect that was attenuated by gonadectomy in females, but
not males.
Further evidence for the disparate susceptibility of
females to PS was shown in stress-induced elevations of
calbindin D28K, a protein that regulates apoptosis [61]. Both
sexes showed reduced calbindin in the medial basal
hypothalamus after moderate or lengthy heat-illuminated
restraint stress to the dam during the last week of gestation,
but males had with higher baseline levels of this protein
[61]. It was suggested that sexually differentiated calbindin
in this region regulates sexual dimorphism of the hypothalamic sexually dimorphic nucleus preoptic area (SDN
POA) nucleus [3], and may serve as a mechanism for
modulation of sexual behaviour in PS offspring. A seminal
study by Ward and Weisz [129] indicated that PS had
demasculinizing effects on male offspring; however, a
discussion of the effect of PS on sexual behaviour is beyond
the scope of this review.
2.3. Effects of PS on modulatory neurotransmitters
The levels or function of monoamines in the brain have
been shown to be affected by mild to severe PS. Regionally
specific alterations in norepinepherine (NE) and dopamine
(DA) turnover were observed after PS, including reduced
levels of NE in the cortex and locus coeruleus (LC), reduced
levels of DA in the LC, but not the cortex [121], reduced DA
turnover in the striatum and nucleus accumbens and
increased DA turnover in the prefrontal cortex [132].
Similarly, administration of the CORT analogue dexamethasone on days 17 19 of gestation, elicited regionally
specific changes in levels of monoamines and their
metabolites in male offspring [82]. Hippocampal and
cortical NE were reduced at different time points. DA was
reduced in the hypothalamus, but elevated in the striatum.
PS induced by crowding and daily saline injections
increased plasma tryptophan in the mothers, and increased
serotonin (5-HT) in foetal brains and postnatally in the
cortex [88]. PS had an age-dependent biphasic effect on
hypothalamic 5-HT, 5-hydroxyindoleacetic acid (5-HIAA),
and NE. At age 9 or 16 days, hypothalamic levels of these
monoamines were lower than controls, but at 23 or 60 days
they were higher. In contrast, 5-HT, 5-HIAA and NE were
increased in cortex and pons-medulla, only up to age 16


O. Kofman / Neuroscience and Biobehavioral Reviews 26 (2002) 457470

days. PS offspring showed greater elevations in the CORT

response to an acute injection of saline stressor at age 23
days, but a reduction in hypothalamic 5-HIAA and NE [89].
Reduced hypothalamic 5-HT was also observed after
prenatal administration of dexamethasone to the dam [82].
PS also increased the behavioural serotonin syndrome
response to a 5-HT agonist as late as age 60 70 days [90].
Since serotonin is implicated in affective and mood
disorders in humans, PS-induced modification of brain
serotonin may predispose offspring to be more sensitive to
stress (see below).
PS enhanced evoked acetylcholine release in the
hippocampus, following intracerebroventricular (icv)
microinjections of saline in males only or icv CRF in both
sexes [24]. PS also reduced the number of hippocampal
benzodiazepine receptors in rats [39]. In conclusion, despite
the large variability in severity, duration and timing of the
PS administered in the studies cited earlier, it is clear that PS
leads to age-dependent perturbations in the development
and function of major modulatory neurotransmitter systems.

experimenter-induced stress interacted to enhance or

interfere with the performance of rats [79,135] or monkeys
[5] on a working memory task. An inverted U-shaped curve
was obtained such that low doses of D1 receptor agonists
enhanced working memory, whereas high doses of the D1
agonist or more severe stress impaired working memory.
Stress in adult rats also stimulated the release of DA in the
PFC, especially on the right [12]. Right hemisphere DA
dysfunction has been reported in the midbrain of children
with attention deficit hyperactive disorder (ADHD) [36] and
PFC DA was linked to disorders of executive functions in
children with phenylketonuria (PKU) [29]. These studies in
adult animals and in children suggest that alterations in DA
function or laterality induced by PS could have far-reaching
implications in the aetiology of behavioural disorders in

2.4. Changes in motor lateralization and dopamine


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
monkeys 72 h before delivery resulted in reduced density
of the pyramidal neurons and reduced thickness and
circumference of the cornus Ammon (CA) and dentate
gyrus regions of the hippocampus. In animals whose
mothers were treated for 30 days with dexamethasone, the
entire hippocampal formation was smaller than that of
controls, with a dose-related loss of neurons.
In rodents, PS induced significant alterations to the
hippocampus and dentate gyrus. Restraint stress three times
daily in the last trimester of pregnancy in rats resulted in
reduced cell proliferation in the dentate gyrus, which was
evident throughout the lifespan. In particular, there was a
decrease in the number of granule neurons between 3 and 22
months of age and a marked absence of hippocampal
neurogenesis in PS rats compared to control rats as a result
of learning a spatial task [60]. PS reduced the density of
nitric-oxide producing neurons in the dentate and part of the
hippocampus [124]. Severe restraint stress during the last
week of gestation did not affect the volume of the sexually
dimorphic medial amygdala, but mild PS (saline injection)
enlarged the basolateral nucleus of the amygdala in adult
offspring [92]. Enlargement of this nucleus, which is critical
for conditioned fear [58], may be related to the changes in
emotional behaviour following PS described later [33,59,84,
PS increased the size of the rostral anterior commissure

PS has been related to changes in the distribution of DA

and its metabolites in the terminal areas. Aside from the
striking fact that females are more affected than males, no
clear lateralization pattern emerges. Unpredictable light
and noise stimulation in pregnant dams decreased 3,4dihydroxyphenylacetic acid (DOPAC) levels and DA turnover in the striatum of females only. This form of PS also
eliminated the left bias in DOPAC/DA ratio in the striata of
female rats [42]. In contrast, Alonso et al. [4] found that PS
female rats had reduced levels of DOPAC and homovanillic
acid (HVA) and higher DA levels in the right, but not left
nucleus accumbens. Several methodological differences
between these studies include the type of stress (unpredictable but moderate in the Fride and Weinstock study as
opposed to severe in the Alonso et al. study), the areas
studied (striatum vs accumbens) and the fact that analysis of
DA levels in the study Fride and Weinstock [42] study
occurred 2 weeks after amphetamine treatment.
Motor lateralization was also found to be altered by PS.
Male and female neonates showed a greater tendency
toward right tail postural bias following PS. In female rats,
PS was reported to elicit either a leftward [42] or a rightward
[4] turning bias. In conclusion, PS appears to alter the innate
pattern of laterality and there is some suggestion that this
altered asymmetry is related to DA turnover. These findings
lead Weinstock [130] to speculate that PS effects on DA
might mediate the development of schizophrenia in
predisposed individuals.
Several preclinical and clinical studies report that
executive functions such as working memory and behavioural inhibition are dependent on prefrontal cortical (PFC)
DA. D1 agonists injected into the prefrontal cortex and

3. PS-induced structural modification of limbic

structures in brain

SD, SpragueDawley; CR, Charles River; M, male; F, Female; , , not significantly different from control group; " , significantly greater than controls; # , significantly less than controls.

M, 70 days
Restraint 30 min/day

17 21 or 17 only (acute)

M and F, 36 months
M and F, 16 and 60 days
15 22
14 20
Restraint 30 min 3/day
Restraint and light 45 min 3/day

Long Evans

M, 90 days
14 21
Restraint and light 45 min 3/day


M and F, 46 weeks
10 18
77 dB sound and swim stress

14 21
Handling, novel cage, saline injection/day randomly


M, 75 100 days

# rearing in non-adopted PS
, baseline activity
" nicotine induced hyperactivity
, baseline activity or rears
" time in dark chamber (defensive withdrawal)
, spontaneous activity
" sound-induced attenuation of motor activity. Greater in M
, baseline activity
, amphetamine hyperactivity first time
" sensitization to amphetamine hyperactivity
# in F but not M
# 16 days
, 60 days
" activity in chronic but not acute
M, 12 weeks
M, 3 months
Mild restraint small cage

15 17

Prenatal stress

Table 1
Summary of the effects of prenatal stress (PS) on locomotor activity

Gestational age at PS


Sex and age at testing

Effect on motor behaviour

O. Kofman / Neuroscience and Biobehavioral Reviews 26 (2002) 457470


(AC) in male, but not female offspring [50]. This could be

interpreted as a demasculinizing effect of PS on males, since
this commissure is larger in females than males in rats [50]
and humans [2].

4. 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
4.1. Motor development and locomotion
Retardation of motor development in children is one of
the major effects cited by Stotts [115] longitudinal study on
birth complications and defects. PS delayed the development of neonatal sensorimotor reflexes [33] in males and
delayed the development of spontaneous alternation behaviour in female rats [39,41]. Inconsistent conclusions on the
effects of PS on locomotion and exploratory behaviour are
liable to be related to variability in strain, method of
measuring locomotion, and type of PS (reviewed in Ref.
[132]). Recent studies applying severe PS, tend to find no
significant difference between unstressed and PS male rats
in baseline locomotion [45,55,59,84,128], although rearing
behaviour in PS male rats was diminished [43,128].
On the other hand, reduced locomotion was observed in
PS females but not males [59] and in both sexes at 16 but not
60 days of age [136]. In contrast, later exposure to daily
stress (GD 17 21), elicited an elevation in locomotion in PS
male rats [134] and in offspring of pregnant dams treated
with dexamethasone on GD 17 19 [82]. All the studies
cited above used restraint stress during the third week of
pregnancy with the exception of Nishio et al. [84] who used
a combination of swim and noise stress. The exact timing of
exposure of the dam to stress may be critical in determining
if baseline activity will be altered in offspring, as the studies
that found no changes or reductions in activity used stress
exposure at an earlier stage of gestation (Table 1).
In contrast to the nebulous findings on baseline
locomotion, PS enhanced sensitization to the locomotor
effects of amphetamine with a concomitant increase of D2
DA receptors and decrease of D3 receptors in the nucleus
accumbens [45]. Similarly, the same lab showed that PS
increased nicotine-induced hyperactivity [55].
Open field activity in a novel environment, is usually
cited as a measure of exploratory behaviour; however, this
measure can be confounded by anxiety in rodents. The
offspring of dams subjected to daily predictable stress in
pregnancy had smaller increases in plasma CORT when
exposed daily to an open field than controls, whereas the


O. Kofman / Neuroscience and Biobehavioral Reviews 26 (2002) 457470

offspring of dams subjected to unpredictable stress had

greatly exaggerated CORT responses, which did not
undergo adaptation [131]. The interaction with anxiety
can also be deduced from the greater inhibition of
locomotion induced by stressors in PS rats [84,128].
4.2. Learning
Perturbances of HPA-axis function have been predictably linked to changes in learning tasks that are dependent
on the hippocampus. In humans GCs have been shown to
interfere with declarative memory [26]. PS retarded the
acquisition of reversal discrimination learning, but did not
affect simple discrimination in a non-spatial operant
paradigm [134]. Spatial learning in water mazes was
retarded in male PS rats, but not in PS females [60,84,118].
Mild PS, however, actually enhanced acquisition and
reduced errors in a radial arm maze [43]. Notably, the latter
study not only used shorter and milder stress, but it also
differed from the other spatial learning studies in that no
swimming was involved in the learning paradigm. Spatial
tasks involving swimming are inherently more stressful than
non-swimming tasks [22]. To illustrate this point, Szuran
et al. [118] found a delay in acquisition of the water maze
only when the water temperature was 10 8C, but not at
20 8C. As outlined in Section 4.3, PS animals appear to be
more vulnerable to various stressors in adulthood. Thus,
spatial learning paradigms that require swimming, such as
the Morris water maze or the swim T-maze, or difficult
tasks, like reversal of a previously learned discrimination,
are more likely to be sensitive to PS than learning paradigms
that are less stressful. Moreover, the enhancing effect of
mild stress is consonant with findings that the effect of stress
on learning fits an inverted U-shaped function, such that
moderate stress facilitates, and severe stress impairs
learning [5,25].
4.3. Behavioural reactivity to aversive stimuli
Converging lines of stress-related research suggest that
PS enhances the response to stress in offspring, although the
findings vary with the type of response measured [119].
Severe PS throughout most of gestation decreased the
ultrasonic vocalizations to tail shock and isolation in male
rats at age 14 days, but at the same time reduced the latency
to tail flick [119]. Adult PS rats showed prolonged freezing
following footshock, with no change in the degree of
ultrasonic vocalization [121]. There was also a greater
tendency toward withdrawal into an unlit chamber [128] and
inhibition of locomotion in a open field in response to loud
noise [84] in PS rats. The baseline startle response was
unaffected by PS; however, prepulse inhibition (PPI) of the
startle response was enhanced in PS rats [59].
In an animal model of anxiety, PS rats spent significantly
less time in the open arms of an elevated plus maze [131,
136]. These studies, together with studies that found

enhanced immobility in the behavioural despair swim test

in both male [33] and female [4] PS rats, suggest that PS
enhances unlearned inhibitory responses to stressful stimuli.
On the other hand, experiments that involve avoidance
learning suggest that PS retards learning of both active [59]
and passive avoidance [33]. These data suggest that PS rats
may be more prone to learned helplessness or despair and
less able to learn avoidance behaviours. As with spatial
learning, mild PS on days 15 18 had the opposite effect to
severe stress and ameliorated active avoidance learning
[43]. Future research in this area should take into account
the effect of PS on nociception, as conflicting results have
been found. PS reduced the latency to react to pain in a hotplate test in mice [114], but not tail-flick in rats [117]. Cold
swim stress-induced analgesia was enhanced by PS in
females, but not males. This effect was abolished by
ovariectomy and restored by estrogen [114].
4.4. Courtship and maternal behaviour
Social stress induced by changing colony-mates during
pregnancy and lactation in guinea pigs resulted in an
immature pattern of courtship behaviour. This was manifested as immature patterns of play behaviour interrupting
the normal sequence of courtship [53]. Although the effects
of prenatal and postnatal stress were not distinguished in
this study, the male offspring of stressed mothers also
showed delayed development of the HPA axis.
Maternal behaviour was not aversely affected in PS
female offspring unless the mothers were challenged by
aversive stimuli. PS offspring were more likely to fail to
retrieve their pups if they had to cross an aversive air stream
[39] and were less likely to attack a male intruder [87].
The role of maternal behaviour has also been targeted as
a putative mediating factor in determining the reactions of
offspring to stress. Maternal care in rat pups modifies spatial
learning and synaptogenesis [63]. Fostering enhanced
maternal behaviours such as contact time and retrieval of
pups [68]. Cross-fostering PS rats to a control mother
mitigated some, but not all, hormonal and behavioural
effects of PS [40,43,68]. These studies suggest that maternal
behaviour is an important mediator, but not the sole
determinant of the behavioural effects of PS.

5. 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 11b-HSD type 2 [69,133]. This
enzyme has less activity for synthetic than for endogenous

O. Kofman / Neuroscience and Biobehavioral Reviews 26 (2002) 457470

GCs, which may account for the effects of exogenous GCs

on offspring. Nonetheless, endogenous maternal CORT is
thought to mediate the PS hormonal response in offspring.
Adrenalectomy (with corticosteroid replacement) prevented
restraint stress-induced hormonal changes in PS offspring
compared to the PS offspring of intact, but stressed dams.
Thus, the stress-induced surge of maternal CORT is critical
to the development of the PS response [8,68]. Indeed, the
effect of adrenalectomy was reversed by the injection of a
high dose CORT to the dam. The effects of PS in rodents
were also mitigated pharmacologically by the CRF
antagonists D-phe-CRF or ah-CRF [128], by diazepam
[33] as well as by the steroid neuromodulator pregnalalone

6. 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 mothers showed more
anxiety-related behaviour disturbances [99], the potential
adverse effect of the stressed mothers maternal behaviour
was eliminated by raising both the PS and control monkeys
in a nursery with a cloth surrogate.
Chronic social stress in pregnant squirrel monkeys once
before conception and twice during pregnancy was induced
by changing housing conditions, necessitating the establishment of a new social hierarchy. PS offspring, raised by their
biological mothers, did not differ from controls in body
weight, but had delayed motor maturation, were less active,
had shorter attention spans, lower duration of orienting,
poorer balance and shorter postrotary nystagmus than
monkeys born to unstressed mothers [101]. Prenatal
transporting plus noise stress in Rhesus monkeys (Macaca
mulatta ) led to lower muscle tone, poor balance, greater
passivity and distractability in infants and elevated anxiety
and emotionality at 6 and 8 months in nursery-reared rhesus
monkeys [98 100]. The latter included abnormal behaviour
amongst peers, such as increased sleeping during playtime,
increased clinging and self-clasping, less climbing and
exploratory play, as well as more self-directed mouthing
and clasping when separated from other monkeys. Interestingly, emotional reactivity was sexually dimorphic in
primates, with PS females showing waning disturbance
behaviour over sessions while males showed progressive
exacerbation of this behaviour [98]. A subsequent study by
Schneiders group found no effect of gender on behavioural
reaction to PS [100].


The effects of PS were also examined up to adolescence

(4 years) in rhesus monkeys. PS elicited more locomotion,
but less exploratory behaviour and more stereotyped
behaviour, self-clasping, freezing and general disturbance
behaviour in an unfamiliar environment or social setting
[21]. These monkeys also showed less play and social
interaction, and less contact time in proximity to cagemates.
This PS regimen also resulted in enhanced ACTH, but not
cortisol secretion under baseline or stress conditions,
suggesting impaired HPA feedback [22]. More recently,
Schneider et al. [103] found that offspring of rhesus
monkeys exposed to stress in early gestation had more
marked attention deficits and motor delays than those
subjected to PS in mid- to late-gestation.
Changes in biogenic amines in cerebrospinal fluid (CSF)
of rhesus monkeys suggested that, as in rodents, PS alters
the development of modulatory neurotransmitter systems.
PS monkeys had elevated baseline 3-methoxy 4-hydroxyphenylglycol (MHPG) and DOPAC and elevated stressinduced MHPG and NE in comparison to controls [100].
Individual levels of MHPG and NE during separation stress
at 8 and 18 months were positively correlated, whereas the
baseline levels were negatively correlated. This suggests
that some adaptation occurred for baseline levels, but not for
reactivity to stress. The effects of PS were mimicked by
administering ACTH for 14 days to monkeys in midgestation, suggesting that the hormonal response of the
mother mediates the changes observed in the offspring
[102]. At 2 weeks of age, infants exposed prenatally to
higher levels of ACTH had delayed motor development,
shorter attention spans and increased irritability.

7. How relevant are prenatal stress studies in laboratory

animals to human development?
7.1. Developmental sequelae to steroid administration in
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 deliver prematurely [133]. GCs reduce respiratory
difficulties and enhance the chances of survival in premature
infants. Several studies have examined the short- and longterm effects of administration of synthetic GCs, such as
dexamethasone and betamethasone. Investigation into the
developmental effects of GCs is confounded by the fact that
premature delivery per se is a risk factor for developmental
disorders [28].


O. Kofman / Neuroscience and Biobehavioral Reviews 26 (2002) 457470

When compared to untreated premature babies, premature babies treated with synthetic GCs showed no greater
delays in behavioural development at age 2 years [93], no
difference in the rate of neurological and other disabilities
such as cerebral palsy, vision and hearing disorders at 3
years [38], or on behavioural and IQ measures at 4 years
[66]. However, other studies have linked prenatal dexamethasone treatment to a higher incidence of cerebral palsy
[105]. Smolders de Haas et al. [109] reported that at ages
10 12 premature-born children treated with GCs did not
differ from untreated premature children on neurological
and sexual development, although they did have a history of
more frequent infectious diseases (excluding otitis). This
could be related to the immunosuppressive effects of
One of the methodological pitfalls of studies that
compare prematurely born children who were treated with
steroids to untreated children is that steroid-treated babies
tend to have a higher incidence of low birth weight, and
small head circumference than the untreated premature
babies [66]. This has been variously attributed to suppression of foetal growth by GCs [19] or to the fact that GCs
decrease respiratory problems, enhancing the survival rate
of low-birthweight infants. Decreased cognitive performance has been found to be related both to low birthweight
and to small for gestational age size at the time of premature
delivery [70], suggesting that birthweight is a mediating
factor to be considered in longitudinal assessment of
steroids in pregnancy.
MacArthur et al. [66,67] conducted a longitudinal
follow-up of a cohort of premature children, who were
either treated with betamethasone or untreated during
gestation. At age 4 years, before entering school, there
were no differences in the cognitive and social development
between the two groups; however, at age 6 years (during the
first year of school) some cognitive differences emerged.
Boys, but not girls pretreated with betamethasone, had
lower scores on Ravens Progressive Matrices, a test of
reasoning ability, and on two tests of visual closure [67].
When birthweight and gestational age were controlled by
using a matched control sample, only the difference in the
Ravens Progressive Matrices remained. The authors of this
study concluded that the betamethasone treatment
accounted for 25% of the variance on the Ravens test.
While the majority of studies do not suggest that exogenous
GCs in late pregnancy have deleterious effects on development, the studies cited above did not usually test higher
cognitive functions or performance under stress. Notably,
this study found a gender difference similar to that which
had been found for emotionality in PS monkeys [100] and
for spatial learning in PS rats [84,118]. The few examples of
an interaction between sex and PS on cognitive and
emotional development suggest that this issue should be
more thoroughly elucidated both in preclinical and clinical
The fact that the Raven Progressive Matrices, which

involves abstract reasoning, was affected in the MacArthur

et al. [67] study suggests that this test was more sensitive
than the standard IQ and behavioural development tests
used at younger ages. Reasoning and other executive
functions such as working memory, inhibition of irrelevant
behaviours, and phonological fluency, have been related to
activation of the prefrontal cortex [9,11,106,126]. Myelination in humans begins at the end of the second trimester of
pregnancy, but progresses at different rates in different
cortical areas well into adolescence [46,112]. Cognitive
deficits dependent on prefrontal cortex might emerge during
the early school age years, as more demand is made on the
use of executive functions. In sheep, prenatal administration
of corticosteroids was found to slow the process of axonal
myelination of the optic nerve [34]. Further studies are
required to determine if PS has long-term effects on
myelination in primates.
7.2. Developmental sequelae to prenatal stress in infants
and children
Although the evidence for the detrimental effect of PS on
learning and emotional behaviour in preclinical research is
compelling, most studies on the long-term effects of
maternal stress in infants focussed on pregnancy and
delivery complications and birth weight, but not on later
cognitive and emotional development in the child. Several
methodological issues should be considered when addressing this issue, since the methods used vary considerably
with respect to (a) the instruments used to assess maternal
stress, (b) the gestational period at which maternal stress
was assessed, and (c) the outcome measures in infants and
children. Lobel [64] reviewed the problems and concerns
inherent in measuring outcomes of PS in humans. Stress is
generally assessed on the basis of life event or anxiety
questionnaires, but the response to stress varies greatly
across individuals, interacting with trait anxiety, precipitating events, coping mechanisms and support from the
environment. Most of the research in this field clearly
indicates that subjectively perceived stress is a greater
determinant of the various outcome measures than are
measures of stress that are based solely on an objective
severity scale.
Despite unresolved methodological issues, several
studies point to an effect of subjective and social stress on
infant size and health. In a longitudinal survey of birth
complications and infant morbidity in Glasgow between
1965 and 1966, marital discord and personal tensions were
highly associated with child morbidity [115], while
externally perceived stress (e.g. death of a mothers relative
during pregnancy) had no significant overall effect.
Morbidity measures included motor delays, behavioural
disturbances, malformations, failure to thrive, and neurological disturbances. In particular, the developmental delays
described as late walking or poor walking and congenital
hyperactivity were associated with personal tensions,

O. Kofman / Neuroscience and Biobehavioral Reviews 26 (2002) 457470

which were characterized as continuous or liable to erupt at

any time and that they were incapable of resolution either by
action or by adjusting to them. Stott [115] perspicaciously
observed that the situation of pregnant women suffering
from chronic or repeated marital or interpersonal strife is
comparable to that of laboratory rats exposed to electrical
shock. He emphasized that it was the subjective perception
of control over the situation and not the objective severity of
the situation that led to morbidity and concluded that
the association between personal tensions during the
pregnancy and hyperactivity in the child appears to be a
very close one. This by no means establishes prenatal
psychological stress as a factor in behavioural disturbances.
As Stott pointed out, marital discord and personal tension
were also highly associated with low socioeconomic status,
factors which would continue to play a significant role in the
childs development.
Birth/pregnancy complications were found not to be
related to life changes [85], but a more recent study
showed that less participation in social events and poor
social stability were risk factors for giving birth to small for
gestational age babies, even when factors such as height,
weight, and smoking were factored out [27]. Immigrant
women, as opposed to native-born Swedish women, were at
higher risk for scoring lower on the total support factor and
for giving birth to small for gestational age babies.
In adolescent mothers, negative emotionality (a composite of depression, anxiety, hostility and anger) during the
first 16 weeks of gestation was associated with higher Agpar
scores in infants at 5 min, but lower infant vagal tone.
However, higher levels of salivary cortisol in early
pregnancy predicted lower Agpar scores. The dissociation
between questionnaire-based assessment of negative emotionality and cortisol levels emphasizes the need to
standardize testing procedures for maternal stress and to
use multiple measures.
The time of assessment of maternal stress is another
critical variable that has to be taken into account when
assessing the research in human foetuses. Negative
emotionality in the mother in the third trimester was
correlated with a greater number of abnormalities in the
newborn, despite the fact that this same measure in early
pregnancy was associated with high Agpar scores [91].
Maternal dysphoria at the time of birth was also associated
with a longer duration of infant crying in the first 6 h after
birth before the infants had significant interaction with their
mothers [86]. Moreover, higher stress levels in the mother in
the early to middle stages (16 20 weeks) of gestation were
positively correlated with difficult temperament and lack of
hedonia at 6 months, but negatively correlated to scholastic
achievement and behaviour at an age of 7 years [83]. It is
possible that a negative emotional state in early pregnancy
leads to adaptive mechanisms, which curtail some, but not
all of the behavioural effects of stress on the foetus. Further
research is required to compare the effects of maternal stress
at different stages of gestation. The studies cited above


focussed on delivery complications and foetal size as

measures associated with maternal stress during pregnancy;
however, more normative manifestations of maternal
anxiety in healthy pregnant women have been revealed
through foetal monitoring of movement and heart rate
during the last weeks of pregnancy.
7.3. Foetal heart rate and movement as indices of central
nervous system control
As early as 1941, Sontag [111], in his review of the
effects of foetal environment on birth outcome, stated that,
Deeply disturbed maternal emotion produces a marked
increase in activity of the fetus, probably as a result of
increased adrenalin level in the maternal and, therefore, the
fetal blood. Sontag recorded increases in foetal activity in
stressed mothers and speculated that during the later months
of pregnancy the balance of parasympathetic sympathetic
tone in the autonomic nervous system is established. At that
time critical time he concluded, Prolonged nervous and
emotional disturbances of the mother during the later
months of pregnancy can lead to autonomic instability,
including digestive and cardiovascular symptoms in the
Today, several clinical measures of foetal development
have been adapted as research tools to study maternal
foetal interactions under stressful conditions. These
measures include baseline heart rate and stimulus-induced
heart rate acceleration and deceleration, stimulus-induced
movement, and habituation and dishabituation to the above
measures [55]. The human brainstem develops in a caudal
rostral direction, with spontaneous movements occurring by
the age of nine gestational weeks. Maturation of the foetus
can be measured by (a) frequency of autonomic reflexive
movements, such as breathing movements, (b) frequency of
gross motor movements of the head, trunk and extremities,
(c) the degree to which these movements become coupled to
arousal and foetal heart rate (FHR), and (d) establishment of
diurnal variability in these functions [55]. Parasympathetic
control of FHR is dominant up to 25 weeks gestational age,
at which time the emergence of sympathetic control and
FHR accelerations are observed [55]. By about 20 weeks
gestational age, there is an increase in the coupling of FHR
acceleration to movement, and at term FHR accelerations
occur concomitantly with movements and increased arousal
[31]. Towards term, the synchrony between heart rate
accelerations and movement increases, similar to the pattern
in the neonate. This coupling is considered to reflect central
nervous system maturation and control [31,32,55].
A further sign of foetal maturity is the emergence of
environmentally induced changes in FHR and movement
around the 26th week of gestation, along with the
maturation of the pons [52]. By the 36th week, the acoustic
nerve is developed enough to enable the foetus to
discriminate sounds. Accelerations and decelerations of
FHR have been used to measure inchoate cognitive


O. Kofman / Neuroscience and Biobehavioral Reviews 26 (2002) 457470

functions such as attending or discrimination of sounds such

as its mothers voice, habituation (non-associative learning)
to repeated stimuli and dishabituation [52,55,94]. Learning
at this stage is concomitant with the experience-shaped
synaptic pruning and growth of dendrites that begins in
gestation and continues postnatally.
7.4. Foetal behavioural response to maternal anxiety
A correlation was found between the mothers state
anxiety score and foetal movement in healthy, non-anxious
women [125]. Di Pietro et al. [31,32] reported that
subjective stressors (both positive and negative) in healthy,
non-smoking, pregnant women reduced heart rate variability, and heart rate foetal movement coupling in the
foetus. Perceived stress, as measured by anxiety questionnaires and life event scales, was positively correlated to
plasma ACTH in pregnant women. Conversely, pregnancyrelated social support was negatively correlated to ACTH
and cortisol levels, whereas general social support (unrelated to the pregnancy) was negatively correlated to the
mothers plasma b-endorphin and cortisol levels [94]. The
level of the mothers plasma b-endorphin in the third
trimester was positively correlated to the FHR reaction to a
novel stimulus after habituation to a repeated vibro-acoustic
stimulus. This association between the mothers reaction to
stress and foetal CNS reactivity [94] is consistent with
Sontags [111] speculation that maternal stress can interfere
with the normal development of autonomic regulation
mediated through hypothalamic and brainstem mechanisms.
One study of extraordinary stress found that foetuses of
pregnant women during an earthquake in Italy showed
vigorous and disordered motor hyperactivity lasting from 2
to 8 h [48].
Evidence for a role of maternal trait anxiety in foetal
autonomic control has also been reported. Cognitive
stress, induced in healthy pregnant women at 35 38
weeks by mental arithmetic and Stroop colour naming
tasks, increased maternal systolic and diastolic blood
pressure only in mothers scoring below the group
average on the Speilberger State Trait Personality
Inventory. Both high and low anxious mothers showed
increased respiratory rate and no change in heart rate
during the cognitive challenge [80]. In contrast, the
foetuses of high-, but not low-anxious mothers showed
significant increases in heart rate during the 5-min
cognitive stress trial. This study indicates that during
this stage in development, foetal reaction to the
mothers stress remained robust even when the maternal
pressor response had habituated to her state of anxiety.
Maternal trait anxiety has also been linked to altered
distribution of foetal blood flow and small for gestational age body weight. Trait, but not state anxiety was
significantly correlated with a lower pulsatility index in
the foetal middle cerebral artery [107].

7.5. Conclusions
How relevant are the effects of PS in laboratory animals
to the role of PS as a predisposing factor in the development
of behavioural disorders in children? Evidence of changes
in FHR [31,32,80,94,107] and movement [125] suggests
that maternal trait and state anxiety during pregnancy can
interact to modulate the FHR response to external
stimulation. This suggests, that the foetus is affected by
the maternal stress response. It is plausible that if
hippocampal development is compromised in the foetus
by stress, as has been suggested by animal studies [60,122,
124], regulation of the HPA axis [72,74,95,96] and
cognitive function may be impaired in the child. Hippocampal function is related to explicit memory in humans
[10], relational learning and spatial learning in rodents [35].
The early hippocampal lesion model for schizophrenia
emphasizes the importance of neural circuits between
ventral hippocampal and prefrontal cortex in regulating
the motor response to DA agonists in adult rats [52,62].
Thus, perturbations of hippocampal feedback mechanisms
could conceivably alter both cognitive and emotional
development as a consequence of maternal anxiety. This
literature has been recently reviewed by Weinstock [130].
Another potential consequence of PS in humans is
related to the development of behavioural inhibition by the
prefrontal (predominantly right) cortex. Prefrontal cortical
DA terminals are thought to be critical for behavioural
inhibition and working memory in infants [29] and nonhuman primates [5]. ADHD has been reported to occur in as
many as 5 10% of school-age children and is generally
treated with catecholamine transport inhibitors such as
methylphenidate, which increases extracellular DA [127].
CSF levels of the DA metabolite homovanillic acid (HVA)
were highly correlated with the level of hyperactivity and
were good predictors of the methylphenidate response in
boys with ADHD [16]. The alterations in DA asymmetry
following PS in rodents [41] are reminiscent of the
asymmetric increases in [18F] fluorodopa ([18F] DOPA)
binding in the midbrain of small sample of ADHD boys
studied with positron emission tomography [36]. In this
sample, the increased [18F] DOPA, which measured dopa
decarboxylase activity, was higher in the right midbrain.
Structural differences between ADHD and control children
in the direction of asymmetry of DA-terminal structures
such as the caudate have also been reported [16 18].
Children with ADHD were found to lack the normal R . L
asymmetry in the caudate and to have smaller right
prefrontal lobes [16,17,18], have smaller volumes of the
globus pallidus (particularly on the left) [7]. In boys with
ADHD, reductions in right prefrontal cortex white matter
and left prefrontal grey and white matter were found [54].
Although heritability for ADHD is reported to be
between 0.6 and 0.9 [1], it remains to be determined how
genetic factors interact with the environmental factors
implicated in the aetiology of ADHD [13,37]. ADHD and

O. Kofman / Neuroscience and Biobehavioral Reviews 26 (2002) 457470

impaired emotional regulation in infants has been associated

with the seven repeat allele of the D4 receptor [6,73,81] or
the 480 allele of the dopamine transporter (DAT) [44].
Gestational and delivery complications [37,113], drug use
(including smoking) during pregnancy, low socio-economic
status, marital and family discord, maternal psychopathology and paternal criminality [13,73,77] have all been cited
as risk factors for attention deficit in childhood. PS effects
on DA asymmetry or on delayed myelination [34] are
plausible, albeit conjectural, mechanisms whereby maternal
stress interacts with a genetic predisposition for developmental disorders. It is possible that prospective longitudinal
studies of large samples of infants and children whose
mothers have been subjected to unusual trauma related to
war or natural disasters will shed more light on the role of
maternal stress in development.






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

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