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Infants & Young Children
Vol. 19, No. 3, pp. 246–259
c 2006 Lippincott Williams & Wilkins, Inc.
Prenatal Exposure to Stress
and Stress Hormones
Influences Child Development
Elysia Poggi Davis, PhD; Curt A. Sandman
[AQ1]
Stress has significant consequences throughout the lifetime. However, when it occurs early in
life, the implications may be particularly profound and long lasting. Evidence suggests that high
levels of maternal stress during pregnancy are associated with alterations in the normal activity of
the maternal hypothlalamic-pituitary-adrenocortical (HPA) and placental axis. Increased activity of
this system is related to shortened gestation and impaired fetal growth, factors that place infants
at a greater risk for a wide variety of developmental problems. In addition to the implications for
birth outcome, our findings suggest that prenatal exposure to stress and stress hormones directly
influences development of the fetal central nervous system (CNS). Fetuses that are exposed to
disregulated production of stress hormones display impaired learning. Elevated levels of stress or
stress hormones during pregnancy are also associated with more difficult infant temperament and
disruption of infant HPA axis activity. These data suggest that prenatal experiences can have lasting
implications on development. Key words:
[AQ2]
I
T has become increasingly evident that
the origins of many illnesses begin in fetal
life, and that prenatal events have beneficial
and harmful effects on health (Gluckman &
Hanson, 2004). The influential studies of
Barker (1998) provide convincing support for
the importance of human fetal experience in
determining developmental patterns. The potential vulnerability of the fetus to extrinsic
factors is most apparent when teratogenic
drug or alcohol exposure causes congenital
malformations. However, even more moderate influences, such as stress during pregnancy, have been shown to cause such malformations (Carmichael & Shaw, 2000; Hansen,
Lou, & Olsen, 2000). A range of studies has
implicated intrauterine glucocorticoid (GC)
exposure as one of the key mediators of
the effects of intrauterine deprivation (Butler,
From the Department of Psychiatry and Human
Behavior, University of California, Irvine.
Corresponding author: Elysia Poggi Davis, PhD, UCI
Women and Children’s Health and Well-Being Project,
333 City Blvd W, Suite 1200, Orange, CA 92677 (e-mail:
[email protected]).
246
Schwartz, & McMillen, 2002). We will discuss
the ways that relatively subtle changes in the
maternal/fetal environment relating to prenatal exposure to maternal stress and stress hormones can have profound and permanent influences on fetal growth, the fetal central nervous system (CNS), and subsequent behavior.
PRENATAL STRESS
Prenatal exposure to stress and stress hormones is a risk factor affecting human development. Fetal stress can be defined as any
event that disturbs fetal homeostasis and alters the normal trajectory of development
(National Children’s Study, 2004). Stress any [AQ3]
time during development can have lasting
consequences. However, the effects of stress
may be most harmful when they occur during early development. Stress during the prenatal period may have the most serious consequences. During pregnancy, maternal stress
threatens the fetal nervous system and shortens the length of gestation. Both of these consequences increase the risk that infants are
born with cognitive, physical, and emotional
problems.
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Prenatal Exposure to Stress and Stress Hormones
Maternal stress during pregnancy and
birth outcome
The most well-documented consequence
of prenatal stress is prematurity, an important
indicator of newborn health. Although many
studies examining the effects of prenatal
stress are limited by conceptual and methodological problems (for a discussion of these issues, see Lobel, 1994; Paarlberg, Vingerhoets,
Passchier, Dekker, & Van Geijn, 1995), there
is significant evidence that pregnant women
reporting high levels of stress or anxiety and
low levels of social support during pregnancy
are more likely to deliver earlier and smaller
infants (Copper et al., 1996; Dole et al.,
2003; Feldman, Dunkel-Schetter, Sandman, &
Wadhwa, 2000; Hedegaard, Henriksen,
Secher, Hatch, & Sabroe, 1996; Misra,
O’Campo, &
Strobino,
2001;
Rini,
Dunkel-Schetter, Wadhwa, & Sandman,
1999). It is interesting to note that the
effects of maternal stress during pregnancy
on birth outcome are related to the timing
of exposure. Evidence suggests that stress
has more profound effects when it occurs
earlier in pregnancy. Mothers who were
exposed to the stress of an earthquake during
their first trimester delivered earlier than
those who were exposed during the third
trimester (Glynn, Wadhwa, Dunkel-Schetter,
& Sandman, 2001).
Most important, maternal stress indicates
that these birth outcomes are independent of
established obstetric and sociodemographic
risk factors. Furthermore, the magnitude of
the independent effect size of maternal psychosocial processes in pregnancy on prematurity related outcomes is comparable to that
of most other established obstetric risk factors. These findings suggest that maternal psychosocial processes in pregnancy are important and warrant further consideration.
Maternal stress during pregnancy and
postnatal development
In addition to the consequences for birth
outcome, maternal psychological state during
pregnancy influences fetal and infant devel-
247
opment. Extensive animal studies have documented lifelong effects of exposure to stress
during prenatal development (Chapillon,
Patin, Roy, Vincent, & Caston, 2002; Schneider, 1992; Weinstock, 2001). Much less is
known about the consequences of prenatal
stress for human development. Furthermore,
it is difficult to generalize human populations
on the basis of animal models because of
significant interspecies differences in reproductive physiology as well as the type and
severity of stressors examined.
Human studies have reported that indicators of maternal stress, including anxiety and
depression, during pregnancy shape fetal behavioral patterns (DiPietro, Hilton, Hawkins,
Costigan, & Pressman, 2002; Monk, Myers,
Sloan, Ellman, & Fifer, 2003) and predict
higher cortisol and norepinephrine and lower
Brazelton scores in the newborn (Jones et al.,
1998; Lundy et al., 1999). A small but growing
literature is beginning to demonstrate that the
consequences of prenatal maternal stress persist into the postpartum period (e.g., Luoma
et al., 2001; O’Connor, Heron, Golding,
Beveridge, & Glover, 2002; Van den Bergh,
1990). These studies, however, are often limited by their reliance on retrospective report
of stress during pregnancy or parent report
of child behavior, and thus may reflect differences in the ways that anxious mothers perceive their children.
Recently, several prospective studies have
been performed in which infant behavior is
assessed by an independent observer. These
studies demonstrate that prenatal stress, assessed using both maternal anxiety and the
occurrence of negative life events, influences
both cognitive development and temperament. Pregnant women’s anxiety has been
shown to predict their infants ability to pay
attention as well as their cognitive and motor development (Brouwers, van Baar, & Pop,
2001; Buitelaar, Huizink, Mulder, de Medina,
& Visser, 2003; Huizink, de Medina, Mulder,
Visser, & Buitelaar, 2002). Consistent with
these findings, Laplante et al. (2004) demonstrated that prenatal exposure to a natural disaster predicted impaired performance
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Figure 1. Neuroendocrine interactions between the fetus, placenta, and mother. CRH = corticotropinreleasing hormone; ACTH = adrenocorticotropin hormone; and 11βHSD = 11β-hydroxysteroid dehydrogenase.
on measures of cognitive and language
development. These studies suggest that exposure to prenatal maternal stress impairs
cognitive development. We assessed the impact of prenatal maternal anxiety on direct
observations of infant negative behavioral reactivity in response to challenge. Prenatal
maternal anxiety was significantly related to
infant behavioral reactivity. Most important,
prenatal anxiety accounted for a significant
portion of the variance after controlling for
postnatal maternal anxiety (Davis, Snidman
et al., 2004). These data illustrate that prenatal maternal anxiety exerts persisting influences on human development, using objective measures of infant behavior. However,
none of these studies using objective laboratory measures followed the offspring beyond
infancy. Longitudinal studies utilizing maternal and teacher report measures have shown
persisting consequences of maternal anxiety
during pregnancy for child behavior problems or negative emotionality (Martin, Noyes,
Wisenbaker, & Huttunen, 1999; O’Connor
et al., 2002; Van den Bergh & Marcoen, 2004).
There is a need for further prospective longitudinal studies that use objective assessments
of the child’s behavior to differentiate the ef-
fects of prenatal and postnatal maternal psychological states on development.
The hypothlalamic-pituitaryadrenocortical axis
A primary pathway by which stress effects the fetus is the hypothalamic-pituitaryadrenocortical (HPA) axis (Welberg & Seckl,
2001). Glucocorticoids, cortisol in humans,
are the end product of the HPA axis, one of
the body’s major stress systems. Glucocorticoids are released into the general circulation
and have effects on nearly every organ and tissue in the body (Munck, Guyre, & Holbrook,
1984). Hypothalamic-pituitary-adrenocortical
axis activity is regulated by the release of hypothalamic corticotropin-releasing hormone
(CRH). The CRH is a neuroactive peptide
produced in the hypothalamus and in extrahypothalamic sites. The CRH released from
the hypothalamus stimulates the biosynthesis
and release of adrenocorticotropin hormone
(ACTH) and β-endorphin (βE) from the anterior pituitary. The ACTH triggers GC production and release from the adrenal cortex. As
shown in Figure 1, GCs regulate their own
release by negative feedback actions at several levels of the axis (i.e., hypothalamus and
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pituitary) and at extrahypothalamic sites (i.e.,
hippocampus and frontal cortex) (Jacobson
& Sapolsky, 1991; Sanchez, Young, Plotsky, &
Insel, 2000). In contrast, GCs increase HPA
axis activity through stimulation of the amygdala (Schulkin, 1999).
Consequences of GC release include energy mobilization and immunosuppression
(Chrousos & Gold, 1992). Glucocorticoids
easily pass through the blood–brain barrier
(Zarrow, Philpott, & Denenberg, 1970), and
there are receptors for GCs throughout the
CNS (de Kloet, Vreugdenhil, Oitzl, & Joels,
1998; Sanchez et al., 2000). Glucocorticoids
play a role in the regulation of pregnancy.
In primates, including humans, HPA axis
functioning changes dramatically during pregnancy. In contrast to the negative control on
hypothalamic CRH, GCs stimulate the expression of hCRHmRNA in the placenta (Schulkin,
1999). This allows for the simultaneous increase of CRH, ACTH, and cortisol in the maternal and fetal compartments over the course
of gestation (King, Nicholson, & Smith, 2001).
The hypothlalamic-pituitaryadrenocortical axis and birth outcome
The maternal HPA axis is one mechanism
that has been proposed to mediate the effects
of maternal stress on birth outcome and the
development of the fetus during pregnancy.
It has been well documented that women
who have high concentrations of placental
CRH in their gestational stage are at significantly elevated risk for premature delivery
(Erickson et al., 2001; Hobel, Dunkel-Schetter,
Roesch, Castro, & Arora, 1999; Holzman,
Jetton, Siler-Khodr, Fisher, & Rip, 2001; Inder et al., 2001; McLean et al., 1995; Moawad
et al., 2002; Smith, Mesiano, & McGrath, 2003;
Wadhwa et al., 2004). In addition to their
role in the regulation of timing of delivery,
HPA axis hormones including CRH and cortisol appear to directly impact fetal development (Challis et al., 2001; Hillhouse &
Grammatopoulos, 2002; Smith, 2001). Glucocorticoids are essential for the regulation of
intrauterine homeostasis, and differentiation
and maturation of vital organ systems includ-
249
ing the lungs, liver, and CNS (Mesiano & Jaffe,
1997; Rose, Schwartz, Green, & Kerr, 1998;
Winter, 1998).
Hypothlalamic-pituitary-adrenocortical
axis and fetal and infant development
There is increasing evidence that prenatal
stress has persisting consequences for the
development of the offspring. It has been proposed that the HPA-placental axis is a conduit
for the effects of environmental stress on the
fetus. Research with animals indicates that
during prenatal development, the hormones
of the HPA axis have programming effects
on the developing CNS (Matthews, 2000;
Welberg & Seckl, 2001). The influences of the
intrauterine environment on the developing
human fetal brain are poorly understood. This
is because it is not feasible to perform experimental manipulations to examine the direct
effects of HPA axis hormones on fetal and
infant development. Observational studies
have demonstrated that exposure to elevated levels of maternal HPA axis hormones
during pregnancy impairs fetal learning
(Sandman et al., 2003; Sandman, Wadhwa,
Chicz-DeMet, Porto, & Garite, 1999). These
effects may persist to the postnatal period.
Infants who were exposed to higher maternal
cortisol (de Weerth, van Hees, & Buitelaar,
2003) and CRH (Davis et al., 2005) during
pregnancy display more fussing and negative
behavior when having a bath and display
more difficult behavior as reported by their
mothers.
Summary
Collectively, studies of human pregnancy
indicate that exposure to prenatal maternal
stress and HPA axis hormones has implications for fetal development that persist to
the postpartum period. However, interpretation of these studies is limited for several reasons. First, most studies to date rely either
on retrospective report of stress during pregnancy or on parent report of child behavior. Second, these studies rely on naturally
occurring variations in maternal stress and
stress hormones rather than on experimental
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manipulations. This is problematic because
the effects of stress cannot be separated from
the consequences of other factors that might
contribute to this association such as shared
genes or child-rearing practices. Furthermore,
women who experience greater levels of
stress or anxiety during pregnancy are also
more likely to have higher levels of postnatal
stress and anxiety with implications for child
rearing.
To determine the independent contribution of maternal stress for fetal and infant development, it is necessary to manipulate experiences during pregnancy. This
technique has been implemented in animal
research. One model for examining the consequences of prenatal stress for development involves the administration of stress
hormones, such as GCs during pregnancy.
Such manipulations have been performed
with animals demonstrating lifelong consequences of prenatal exposure to GC treatment
(Weinstock, 2001; Welberg, Seckl, & Holmes,
2001). Clearly, ethical limitations preclude the
administration of GCs to women during pregnancy for experimental purposes. However,
there are populations of women who are exposed to GCs during pregnancy for medical
reasons. In these populations, we can directly
evaluate the impact of GC exposure during
pregnancy on development of the offspring.
PRENATAL EXPOSURE TO
GLUCOCORTICOIDS
Antenatal treatment with synthetic
glucocorticoids
It is the current recommendation that a
single course of antenatal GCs should be
administered to women who go into labor
before 34 weeks’ gestation (NIH Consensus Development Conference, 1995). Synthetic GCs readily pass through the placenta
(Albiston, Obeyesekere, Smith, & Krozowski,
1994; Brown et al., 1996). They are not oxidized by 11β-hydroxysteroid dehydrogenase
into an inactive form (cortisone) as is maternal cortisol (Kajantie et al., 2003; King, Smith,
& Nicholson, 2001). Furthermore, synthetic
GCs have a greater affinity for naturally occurring receptors than cortisol (Ballard & Ballard,
1995). Synthetic GCs are administered to enhance lung maturation (Crowley, 2000). Such
treatment acutely changes the fetal lung structure, resulting in improved lung compliance
and better gas exchange. Prenatal GC treatment has been shown to significantly reduce
the incidence of respiratory distress and intraventricular hemorrhage among infants born
before 34 weeks’ gestation (Crowley, 2000).
Evaluation of the offspring of women who received GC treatment during their pregnancy
is a method that can be used to determine
the consequences of prenatal GC exposure for
development.
Prenatal glucocorticoid exposure
and growth
Although prenatal GC treatment has positive effects on lung functioning, it also
appears to have a negative influence on
growth. For decades, it has been observed
that GC therapy during pregnancy reduces
birth weight in animal models, including nonhuman primates (Ikegami et al., 1997; Moss,
Nitsos, Harding, & Newnham, 2003; Moss
et al., 2001; Nyirenda, Lindsay, Kenyon,
Burchell, & Seckl, 1998; Reinisch, Simon, &
Karwo, 1978). Such effects are most powerful
in the latter stages of pregnancy (Nyirenda et
al., 1998), presumably reflecting the catabolic
actions of GCs that are most manifest during
the phases of maximum fetal somatic growth.
Several recent large clinical studies have provided evidence that antenatal GCs in addition
play a role in restricting human fetal growth
(Bloom, Sheffield, McIntire, & Leveno, 2001;
French, Hagan, Evans, Godfrey, & Newnham,
1999; Thorp, Jones, Knox, & Clark, 2002). In
a large cohort study, French et al. (1999) observed that increasing numbers of antenatal
GC courses were associated with a significant
reduction in birth weight of 9% and a reduction in head circumference of 4%. In a second study of 14,000 infants from 100 neonatal intensive care units in North America, it
was found that antenatal GC treatment was
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independently associated with a reduction
in both birth weight and head circumference (Thorp et al., 2002). The reduction
in head circumference after controlling for
birth weight suggests that antenatal GCs reduce brain growth more than somatic growth.
Furthermore, relatively small reductions in
head circumference are associated with more
significant reductions in intracranial volume
(French et al., 1999).
The suppression of growth by antenatal GC treatment does not appear to persist. It has been shown that there is “catch
up” growth in childhood. Several studies
found no effect of prenatal GC treatment
on height, weight, and head circumference
at 3 to 4 years of age (French et al., 1999;
Hasbargen, Reber, Versmold, & Schulze,
2001), while others found that children exposed to antenatal GCs were taller and heavier at ages 6 and 14 than controls (Doyle, Ford,
Rickards et al., 2000; MacArthur, Howie, Dezoete, & Elkins, 1982). These data parallel the
sheep model, which demonstrates that the
growth restriction that accompanies GC exposure is followed by catch-up growth (Moss
et al., 2001). Even though catch-up growth
occurs, being born small has lasting implications on health later in life. Large epidemiological studies have demonstrated that decreased
birth weight is associated with increased
risk of adult cardiovascular and metabolic
disorders, including hypertension, hyperlipidemia, Type 2 diabetes, and death from ischemic heart disease (Barker, 1998; Godfrey,
& Barker, 2000).
It has been proposed that GCs play a role in
fetal programming. The association between
low-birth weight and adult disease may, in
part, be mediated by overexposure to GCs
during the prenatal period (Welberg & Seckl,
2001). This hypothesis is supported by evidence from animal studies illustrating that antenatal GC exposure can have lifelong effects
on blood pressure (Benediktsson, Lindsay,
Noble, Seckl, & Edwards, 1993; Dodic, May,
Wintour, & Coghlan, 1998), insulin resistance
(Nyirenda, Welberg, & Seckl, 2001), HPA
axis function (Welberg & Seckl, 2001), and
251
the CNS (Bakker, van Bel, & Heijnen, 2001;
Matthews, 2000).
Prenatal glucocorticoid exposure
and endocrine and behavioral
responses to stress
The HPA axis is a primary target for GC
programming. In the rodent, fetal exposure
to GCs leads to lifelong alterations in regulation of the HPA system. Antenatal GC treatment results in elevated baseline plasma corticosterone (Welberg, Seckl, & Holmes, 2001)
and a larger corticosterone response to stress
in rodents (Muneoka et al., 1997). Similarly,
in sheep, exposure to GCs alters HPA responsiveness in the offspring at up to 1 year
of age (Sloboda, Moss, Gurrin, Newnham, &
Challis, 2002). Only one study has assessed
the long-term effects of prenatal exposure
to GCs on HPA axis functioning in nonhuman primates. Pregnant rhesus monkeys were
given a synthetic GC treatment, which was
modeled after the regimen that is currently
given to pregnant women. Their offspring had
elevated basal and stress-induced cortisol secretion at 10 months of age (Uno et al., 1994).
Despite significant evidence from the animal literature that prenatal exposure to GCs
has a persisting influence on the HPA axis,
there have been few studies of this phenomenon with humans. In human infants,
baseline cortisol levels are suppressed for 2
to 7 days after prenatal GC treatment and
subsequently return to normal levels (Ballard,
Gluckman, Liggens, Kaplan, & Grumbach,
1980; Dorr et al., 1989; Kauppila, Koivisto,
Pukka, & Tuimala, 1978; Parker, Atkinson,
Owen, & Andrews, 1996; Wittekind, Arnold,
Leslie, Luttrell, & Jones, 1993). The effect of
antenatal GC treatment on HPA axis reactivity and regulation in response to stress, however, appears to persist beyond the neonatal
period. The cortisol response to the CRH stimulation test was suppressed in infants who
received antenatal GC treatment (Ng et al.,
2002). Furthermore, we demonstrated that a
single course of GC treatment suppressed the
cortisol response to a painful stressor (Davis,
Townsend et al., 2004). To date, there are no
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published studies examining long-term effects
of antenatal GC treatment on HPA functioning
in children.
In addition to direct influences on the HPA
axis, GC exposure impacts the development
of systems involved in the regulation of behavioral stress responses. In animal models,
manipulations that alter GC exposure, such
as prenatal stress, lead to increased behavioral indicators of fear or anxiety in response
to challenges, such as novelty (Schneider,
1992; Ward, Johnson, Salm, & Birkle, 2000;
Weinstock, 2001). Furthermore, administration of GCs to rats for all 3 weeks of gestation or only in the last week increases fear
behavior as indexed by reduced ambulation
and rearing in the open field in adult offspring
(Welberg et al., 2001). Late gestation administration of GCs in addition decreases exploration on an elevated plus maze and reduces
mobility during a forced-swim test (Welberg
et al., 2001). These data suggest that fetal GC
exposure may program increased behavioral
stress reactivity and reduced coping in aversive situations.
Similar to animal models, there is evidence
that prenatal GC exposure increases behavioral responses to challenge in children. Trautman, Meyer-Bahlburg, Postelnek, and New
(1995) assessed a group of children exposed
to GC treatment in early pregnancy because
they were at risk of congenital adrenal hyperplasia, but did not go on to develop this disorder. These children showed increased shyness, emotionality, and internalizing behavior
problems (Trautman et al., 1995). These data
are consistent with studies showing that acute
GC administration increases self-reported negative emotions in adults (Schmidt, Fox, Goldberg, Smith, & Schulkin, 1999) and children
(Bender, Lerner, & Kollasch, 1988). In conjunction, these studies suggest that prenatal
GC exposure plays a role in the development
of behavioral signs of distress and increased
negative affectivity in response to challenge.
Prenatal glucocorticoid exposure
and cognition
There is significant evidence from work
with adult animals demonstrating that acute
exposure to GCs causes impairments on
memory and executive function tasks (de
Quervain, Roozendaal, & McGaugh, 1998;
Lyons, Lopez, Yang, & Schatzberg, 2000; Wolf,
2003). Furthermore, early exposure to manipulations such as prenatal stress, which
are likely to influence HPA axis functioning,
has been associated with cognitive deficits
(Welberg & Seckl, 2001). Consistent with
these studies, prenatal exposure of rats to GCs
led to poorer performance as adults on a spatial memory task thought to involve the hippocampus (Brabham et al., 2000). These studies suggest that one likely consequence of
prenatal exposure to GCs is cognitive impairments.
Human studies aimed at establishing the
long-term consequences of prenatal GC treatment on cognition have yielded mixed results.
Existing research is complicated by the fact
that the children studied were born preterm,
and were therefore already at risk for developmental delays. Despite these limitations,
there is evidence for a persisting influence
of prenatal GC treatment on cognition. In a
group of 6-year-old children, antenatal GC exposure was associated with reduced visual
closure and visual memory (MacArthur et al.,
1982). In addition, 2-year-olds exposed to multiple courses of GCs had an increased risk
of neurodevelopmental delays (Spinillo et al.,
2004). Other studies, however, have demonstrated that prenatal GC treatment has either
no effect on cognition (Collaborative Group
on Antenatal Steroid Therapy, 1984; Dessens,
Smolders-de Haas, & Koppe, 2000) or a beneficial effect for IQ (Arad et al., 2002; Doyle,
Ford, Davis, & Callanan, 2000). These studies assessed a heterogeneous population of
infants born at 23 to 32 weeks of gestation
and included infants who were very ill, and
infants with abnormal cranial ultrasounds in
the neonatal period. These factors may obscure primary effects of GC treatment. A second limitation of existing studies is that they
assess only general intelligence and not specific functions that are particularly likely to
be impaired by elevated GCs. There are a
number of studies with adults demonstrating that exposure to elevated levels of GCs
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impairs memory (Lupien et al., 2002; Monk &
Nelson, 2002; Newcomer, Craft, Hershey,
Askins, & Bardgett, 1994) and executive
functions (Lupien, Gillin, & Hauger, 1999;
Young, Sahakian, Robbins, & Cowen, 1999).
Future studies are needed that assess the
targeted effect of GCs on these cognitive
functions as well as general effects on
IQ.
Prenatal glucocorticoid exposure and
brain structure
Glucocorticoid receptors are widely distributed throughout the brain including the
pituitary gland, hypothalamus, hippocampus, amygdala, and prefrontal cortex (PFC)
(Diorio, Viau, & Meaney, 1993; Jacobson &
Sapolsky, 1991; Sanchez et al., 2000). Glucocorticoids exert a range of effects on the
developing CNS (Korte et al., 1996; Meaney
et al., 1996; Weinstock, 2001; Welberg &
Seckl, 2001), and antenatal exposure to elevated GCs has adverse effects on brain development. In the sheep, antenatal GC treatment leads to acute changes in neuronal activity (Antonow-Schlorke et al., 2001; Schwab
et al., 2001) and decreased brain weight, with
repeated doses having a more profound effect (Huang et al., 1999). Postnatal brain cell
proliferation is decreased in the rodent hippocampus by a dose of GCs that is similar to
the one used in clinical practice (Scheepens,
van de Waarenburg, van den Hove, & Blanco,
2003). In addition, manipulations during the
prenatal and perinatal periods that are likely
to lead to elevations of GCs are associated with an increase in amygdalar volume
(Salm et al., 2004) and a decrease in PFC
GC receptors (Shanks, Larocque, & Meaney,
1995).
Primate studies provide further evidence
for a persisting influence of GC treatment on
the brain. A single course of GC treatment
decreased expression of neuronal cytoskeletal proteins and of the presynaptic marker
synaptophysin (Antonow-Schlorke, Schwab,
Li, & Nathanielsz, 2003), proteins that are necessary for brain development and neuronal
functioning. The hippocampus may be specifically targeted by GCs. In two studies, preg-
253
nant primates were given a dose of GCs in
the early third trimester that was designed
to parallel the course and timing of treatment given in clinical practice. Neural degeneration was seen in the hippocampus of
the offspring at birth. Repeating this course
four times significantly exaggerated this effect
(Uno et al., 1990). In the second study, the offspring showed a 30% reduction in hippocampal volume at 20 months of age compared
with controls with no difference in overall
brain volume (Uno et al., 1994). These data,
indicating that prenatal GC treatment causes
irreversible damage to the hippocampus, are
consistent with a primate study demonstrating that prenatal stress leads to a reduction in
hippocampal volume and a decrease in neurogenesis in the dentate gyrus (Coe, Lulbach,
& Schneider, 2002). In summary, these data illustrate that GCs are powerful regulators of
neural differentiation and maturation in the
primate brain; therefore administration of antenatal GCs used therapeutically in human
pregnancy has the potential to alter brain
structures.
Several magnetic resonance imaging studies have demonstrated structural differences
in the brain of premature infants (Abernethy,
Cooke, & Foulder-Hughes, 2004; Peterson
et al., 2000). Two studies of the human
neonate suggest that prenatal GC exposure
has additional consequences for the brain.
Cerebral cortical gray matter brain volume
was reduced in premature infants treated with
antenatal GCs as compared with untreated
infants (Murphy et al., 2001). In addition,
among 10 near term infants exposed to multiple doses of antenatal GCs, it was found that
complexity of cortical folding and brain surface area were reduced as compared with controls (Modi et al., 2001). Although these studies are limited by their small sample size, they
are consistent with the animal data. To date,
the persisting influence of prenatal GCs on
the brain has not been examined. Animal models and studies with adult humans indicate
that the hippocampus, amygdala, and PFC are
the most vulnerable to prenatal GCs (Salm
et al., 2004; Sanchez et al., 2000). On the basis of these data, future studies should assess
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whole brain volume as well as volume of the
hippocampus, amygdala, and PFC in children
exposed prenatal GCs
SUMMARY AND CONCLUSIONS
Accumulating data support the argument
that prenatal stress has profound and lifelong
consequences for health and well-being. It has
been suggested that the hormones of the HPA
axis including GCs mediate these effects. Examination of the impact of pharmacological
administration of GCs is one method that can
be used to evaluate the influence of stress
hormones on fetal development. Prenatal GC
therapy is a commonly used treatment in obstetric practice. Glucocorticoid therapy improves lung functioning and increases survival
among premature infants born at less than
34 weeks’ gestation. However, exposure to
a pharmacological dose of GCs has risks for
development that are similar to those of exposure to maternal stress during pregnancy.
Both exposure to prenatal maternal stress
(Feldman et al., 2000) and prenatal GC treatment reduce birth weight in human infants
(Bloom et al., 2001; French et al., 1999). Data
are beginning to emerge indicating persisting consequences of both prenatal stress and
GC treatment for other aspects of development including endocrine and behavioral responses to stress, cognition, and the brain.
These studies illustrate the importance of
considering the pivotal role that the prenatal environment plays in shaping health and
development, and demonstrate both the requirement for carefully assessing prenatal history when evaluating children and the need
for prospective longitudinal studies that examine the persisting effects of prenatal exposure to stress and stress hormones for child
development.
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Title: Prenatal Exposure to Stress and Stress Hormones Influences Child Development
Authors: Elysia Poggi and Curt A. Sandman
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