Mothers in Stress: Consequences for the Offspring
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Transcript of Mothers in Stress: Consequences for the Offspring
Mothers in Stress: Consequences for the OffspringMaike Katharina Knackstedt1, Eckard Hamelmann1, Petra Clara Arck2
1Department of Pediatrics for Pneumology and Immunology, University Medicine Charite, Berlin, Germany;2Biomedical Research Center, University Medicine Charite, Berlin, Germany
Introduction
For many years, reproductive immunology focused
on the exploration of mechanism involved in preg-
nancy maintenance. It may now be the time to vary
the angle and have a look at the offspring – survi-
ving non-optimal conditions during pregnancy –
leading us to wonder: ‘Where does health begin?’
or – more importantly – ‘Where does disease start?’
High perception of stress seems to have become a
threat to mankind over the last century, sadly reflec-
ted by a blossoming market of wellness products and
stress-relief spas. Besides numerous publications on
stress-triggered diseases, it is now recognized that
daily hassle and high stress perception during preg-
nancy may alter the health of the growing fetus.1
One explanation may be that job stress and a
more-intense career focus are on the rise resulting in
an increase of maternal age at the time of the first
pregnancy.2,3 Additionally, the exposure to stress-
related factors associated with employment are now-
adays more common compared with earlier times
when women were housewives with no accessory
job career.4
The aim of this review is to summarize and discuss
mediators involved in stress triggered hormone and
immune imbalance during pregnancy, which may
cause maladjustment of the developing fetal
organism.
General aspects of fetal programing
Stress perception during pregnancy may not always
lead to miscarriage or contribute to pregnancy disor-
ders such as pre-eclampsia, preterm parturition, low
birth weight or major congenital malformations.4,5,6
Keywords
Atopy, chronic diseases, cytokines, fetal
programing, pregnancy, stress, stress
hormones
Correspondence
Petra Arck, Charite, Campus Virchow Klinikum,
Medizinische Klinik/Biomedizinisches
Forschungszentrum Raum 2.0549,
Augustenburger Platz 1, 13353 Berlin,
Germany.
E-mail: [email protected]
Submitted March 4, 2005; accepted April 25,
2005.
Citation
Knackstedt MK, Hamelmann E, Arck PC.
Mothers in stress: consequences for the
offspring. AJRI 2005; 54:63–69 ª Blackwell
Munksgaard, 2005
doi:10.1111/j.1600-0897.2005.00288.x
No memories exist on one’s time before birth. However, this does not
imply that the developing fetus is not susceptible to external impulses.
On the contrary, the fetus is extremely vulnerable e.g. to environmental
challenges, and a wealth of data reveals that conditions in utero affect
the health of the fetus before and after birth. Threats for the growing
fetus include psychological challenges perceived by the mother, e.g. high
levels of stress during pregnancy. However, stress experienced during
pregnancy not only leads to pregnancy complications like miscarriage,
pre-eclampsia, preterm parturition, low birth weight or major congenital
malformations, stress also increases the risk of the child to develop dis-
eases in the subsequent periods of life. This condition is termed fetal
programing of adult disease. Programing agents seem to include growth
factors, cytokines and hormones, all of which can be altered by stress.
As a consequence, such ‘stress-modified’ systems of the offspring are
more susceptible to environmental influences during later life, e.g. the
development of atopic diseases upon exposure to antigens. The present
review illuminates the complexity of stress perception on fetal progra-
ming focusing predominately on the onset of atopic diseases on the
background of published evidence from immunology, endocrinology,
neurobiology and neonatology.
REVIEW ARTICLE
American Journal of Reproductive Immunology 54 (2005) 63–69 ª 2005 Blackwell Munksgaard 63
A series of recent findings suggest that environmen-
tal factors during pregnancy are of substantial
importance to the disease risk of the child in later
years.7 To explain these findings, the idea of early
life physiologic programing or imprinting has been
advanced, provocatively suggesting physiologic prog-
raming might be the sole example of Lamarckian
evolution.1 Such programing has been documented
in a variety of systems and reflects the action of a
factor during a sensitive period or window of devel-
opment to exert ‘organizational’ effects that persist
throughout life.1,7,8 Programing agents include
growth factors, cytokines and hormones, all of
which can be altered by stress (Fig. 1).
The malnutrition hypothesis
Maternal stress perception during pregnancy leads to
elevated levels of glucocorticoids, which then inter-
fere with immune reactions during the fetal period
and up to 1 1/2 years post-portal in primates.9,10,11
The majority of the stress-elevated levels of glucocor-
ticoids within maternal circulation will be inactivated
at the placenta, which acts as a feto–placental ‘bar-
rier’ to maternal glucocorticoids.12 However; approxi-
mately 10–20% of the maternal glucocorticoids will
pass into the fetal system. Considering the much
lower levels of glucocorticoids present in the fetal
compared with the maternal circulation, a transfer of
10–20% of maternally derived, elevated glucocortic-
oids likely has a great influence on the glucocorticoid
concentration of the fetus, especially on the fetal hy-
pothalamic-pituitary-adrenal (HPA) axis.13 This over-
flow of glucocorticoids may then lead to prolonged
activation of the fetal HPA-axis, which has been
shown to contribute to fetal growth retardation
in utero. In small for gestational age (SGA) children,
increased levels of cortisol releasing hormone (CRH),
adrenocorticotropic hormone (ACTH) and glucocorti-
coid concentrations have been documented.14 Con-
sistently, low birth weight was observed in prenatally
stressed mice. A time period of 3 weeks postpartum
was needed before the stressed pups to catch up and
gain weight to similar amounts as the non-stressed
littermates.15 In experiments with rats, excessively
increased levels of glucocorticoids did not only retard
fetal growth but also caused an increase in blood
pressure probably because of glucocorticoid mediated
alteration of the vascular structure – predominantly
loss of elasticity.16 Reduced blood circulation during
second and third trimester of pregnancy lead to
insufficient supply with nutrients and oxygen to the
rapidly growing fetus. In order to protect the central
nervous system (CNS) from any damage, the fetal
circulation is centralized in benefit of the brain, leav-
ing the abdominal organs exponentially ‘undernour-
ished’.17 Hence, the growth of the abdominal organs
is disrupted resulting in a reduced amount of the cel-
lular content of the organs and a change in their dis-
tribution of cell types.18 This results in the typical
disproportionate size at birth with a big head and a
small body.19 Not only the gross anatomy of the fetus
is affected, but also hormone interactions, metabolic
activity and organ structure. Indeed, the elevation of
glucocorticoid concentration in the maternal circula-
tion after stress perception has detrimental effects on
the growth hormone secretion of the fetal pituitary
gland. Most likely, negative feedback mechanism
suppress growth hormone release, especially insulin-
like-growth-factor 1 (IGF-1), which is a key mediator
of growth and organ development during fetal
life.20,21
A prolonged phase of malnutrition in utero will
finally lead to fetal growth restriction. Such a growth
retardation is associated with an altered insulin
response to glucose.22 The thin neonate lacks skel-
etal muscle as well as fat, and therefore, the periph-
eral need for insulin is dramatically decreased.23
Epidemiological studies demonstrated reduced glyco-
lysis in the muscle of adults with low birth weight
pointing towards a long-term damage with altered
insulin response. In prenatally stressed rats, low
levels of glucose were detected at term. This meta-
bolic alteration was transported into adult life shown
by hyperglycaemia, glucose intolerance and
decreased basal leptin levels.24 A reduction in circu-
lating insulin not only leads to a pathological glucose
utilization but also slows down cell division as insu-
lin is an important growth factor.23
These profound alterations demonstrate a ‘progra-
ming’ of the fetus on suboptimal nutrient exploita-
tion, leading to a ‘thrifty’ state of metabolism.25
Thus, maternal stress during pregnancy affects the
way a child will process, store and utilize energy.
This altered metabolism may program the child to
expect food shortage and to hoard calories. Hence,
these children are more likely to be overweight or
obese and are predisposed to an increased risk of
type II diabetes.
Historically, the first evidence that early develop-
ment could be involved in subsequent, adult
susceptibility to type II diabetes and its consequent
KNACKSTEDT ET AL.
64 American Journal of Reproductive Immunology 54 (2005) 63–69 ª 2005 Blackwell Munksgaard
risk for coronary heart disease came from studies
of men in Hertfordshire.22 Among these 16 000
men born between 1911 and 1930, those with a
birth weight <2500 g showed an increased risk of
coronary heart disease. This risk was statistically
only linked to low birth weight but not to preterm
deliveries or maternal smoking during pregnancy.
Adult life habits, especially obesity, do influence
the individual risk, but the highest risk for coron-
ary heart disease in this study remained low birth
weight.22
The immune imbalance hypothesis
Interestingly, the increase in maternal stress percep-
tion has recently been shown to cause a decrease of
the pregnancy supporting hormone progesterone.26
Such low levels of progesterone and subsequently
progesterone induced blocking factor (PIBF) challenge
maternal tolerance mechanism by priming the mater-
nal immune system towards a pro-inflammatory,
Th1-cytokine response instead of inducing preg-
nancy benevolent Th2-cytokines.26,27 Next to a well-
Stress
HPA - axis ↑
CRH ↑
Progesterone, PIBF ↓
Th2 ↓
Th1 ↑
TNF - α ↑
Fetal growth restriction
Growth factors ↓
Glucocorticoids ↑
Glucocorticoids ↑
Th1 ↓
Th2 ↑
Atopy: e.g.Atopic dermatitisAsthma bronchiale
Type-II-diabetes , elevated blood pressure
Coronary heart disease
Placental blood flow ↓
Mo
ther
Fet
us
Impaired organ development
Vulnerability to disease
Placental apoptosis
Fig. 1 Maternal stress perception leads to prolonged activation of the HPA axis within the maternal organism. This induces increased levels of
CRH. CRH is on the one hand well known to suppress progesterone secretion and therefore diminishes the levels of progesterone induced block-
ing factor (PIBF), an important immune modulator during pregnancy. On the other hand CRH leads to an augmentation of circulation glucocortic-
oids This leads to a shift from Th2 to a Th1 immunity resulting in excessively increased expression of TNF-a at the feto–maternal interface.
Elevated expression of TNF-a has been associated with an increase of cells undergoing apoptosis in the placenta as well as priming the fetal
immune system. Most likely, high levels of Th1 cytokines at the feto–maternal interface evoke counteracting mechanism leading to immunosupres-
sion. A predisposition of the immune system towards atopic disease may be the consequence. On the other hand augmented levels of glucocor-
ticoids have a negative feedback on growth hormone release leading to fetal growth restriction. Low birth weight predisposes to type II diabetes,
elevated blood pressure and obesity leading to a significantly increased prevalence of coronary hear disease.
STRESS AND FETAL PROGRAMMING
American Journal of Reproductive Immunology 54 (2005) 63–69 ª 2005 Blackwell Munksgaard 65
balanced equilibrium of Th1/Th2 cytokines, several
other mechanism are substantial for the success of a
pregnancy.28–30 Such tolerance mediating mechanism
include an up-regulation of immune suppressive
cd-TCR positive T-cells,31 an increased expression of
indolamine 2,3-dioxygenase (IDO), which is able to
deprive T-cells from tryptophane and subsequently
inhibit lymphocyte proliferation,32–34 the presence of
regulatory T-Cells (Treg).35,36 To maintain such mech-
anism of tolerance, the suppression of adhesion mole-
cules such as ICAM-1 and LFA-1 is required.37 These
tolerogenic impulses are disrupted by stress perception
during pregnancy.
Strikingly, data in rhesus monkeys point towards
an important influence of maternal stressduring
pregnancy on the child’s immune development.
When pregnant rhesus monkeys had been stressed,
the offspring showed lower levels of Th1 cytokines,
especially TNF-a, in response to LPS.38 Therefore
maternal stress known to cause an immense increase
of Th1 cytokines at the feto–maternal interface,39–40
does not prime the immune system of the child
towards a Th1 immune response as shown in the
monkeys.
At birth the immune system of the neonate is
primed towards a Th2 dominance. Within the first
2 years of life the immune system is activated, prob-
ably via childhood infections, leading to a naturally
occurring shift from Th2 to Th1 immunity. Maternal
stress during pregnancy may delay this crucial part
of postpartum immune adaptation.41 Although this
may appear highly speculative, it is important to
state that it remains unknown why atopy predis-
posed children do indeed show this delay in the shift
towards a Th1-predominance. Accordingly, an
increased production of Th2 cytokines such as IL-4,
IL-5, IL-9 and IL-13 has been described in those
newborns and infants that later developed atopic dis-
eases.42 Th2 primed T-cells producing high levels of
IL-4 accompanied by high serum levels of IgE and
increased numbers of eosinophils immunological
predispose these children to the onset of atopic dis-
eases. Especially ostentatious is that the risk to
develop an atopic disease is more likely if the
mother, but not the father, suffers from allergies.
Genetic predisposition does not satisfactorily explain
this discrepancy in relevance of maternal to paternal
atopy. Most likely, additional environmental factors
during pregnancy aggravate the genetic predisposi-
tion passed by the mother, for example maternal
stress.43
As a retrospective assessment revealed, maternal
psychological stress is one important predicitve fac-
tors for preterm birth, generally accompanied with
low birth weight. In this context, it seems puzzling
that infants with very low birthweight demonstrate
a low 1-year prevalence of atopic eczema.44 In con-
trast to the data of the prenatally stressed rhesus
monkey the imunological, inflammatory triggers
leading to preterm birth in humans seem to protect
the children from atopy. One possible explanation
for this contradicition may be the heterogenitiy of
factors leading to preterm birth including also non-
immunological conditions such as anatomical predis-
position pregnancy complications. Further, children
with a very low birth weight received a multitude of
pharmacological interventions, which is likely to
interfere with the endogenous immune response.
The enormous augmentation of atopy seen in the
U.S. as well as Western Europe seems to be associ-
ated with western life styles and living conditions.45
One of the possible explanations is the parallel
decrease in early immune stimulatory signals, e.g. by
childhood infections. This observation has lead to
the ‘hygiene hypothesis’ – suggesting that the appar-
ent inverse relationship between childhood infection
and the subsequent occurrence of atopic disease is
one plausible explanation of the rise in atopic dis-
eases.46,47 Another suggestion is that immune stimu-
lation delivered by the gastro-intestinal flora may
influence the immune reactivity towards allergens.
In this line, high amounts of certain bacterial strains
such as lactobacilli and bifidio bacteria in fecal sam-
ples of infants were shown to be associated with
decreased risk rates to develop allergic sensitization
or atopic dermatitis48,49 Interestingly, prenatal stress
exposure significantly reduced the colonization of
the gut with lactobacillus and bifid bacteria in young
rhesus monkeys.50 Further, in animal models as well
as in clinical trials the application of high doses of
lactobacillus and bifid bacteria had a protective effect
on the development of atopy.51,52 Thus, the dis-
turbed immune balance with a lack of Th1 immu-
nity of the offspring in response to maternal stress
in utero in combination with depleted bacterial col-
onization in the gut may enhance the individual risk
for atopy in the child.
But the boundaries of the Th1/Th2 paradigm
might be too limited to explain the effects of prena-
tal stress on the fetal immune system as indicated by
the conflicting data observed in prenatally stressed
rhesus monkeys and the observation of a reduced
KNACKSTEDT ET AL.
66 American Journal of Reproductive Immunology 54 (2005) 63–69 ª 2005 Blackwell Munksgaard
onset of atopic eczema in preterm children. In the
field of allergic research the hygiene hypothesis is
vividly discussed as being an over-simplification.
One important reason for this discussion is contribu-
ted by epidemiological observations demonstrating
that not only Th2 triggered diseases such as atopy
are on the rise but also Th1 triggered autoimmune
diseases.53 Therefore the hypothesis of the mere lack
of an adequate Th1 stimulus during the first 2 years
of life may explain the increase in atopy but does
not give any explanation for the augmentation in
autoimmunity. Parallel to the discussion in the field
of allergy, the paradigm of pregnancy as a pure Th2
phenomenon has been recently challenged as it fails
to satisfactorily explain the complexity of pregnancy
relevant immune adoptions.
In the allergic research field the ‘counter-
regulation hypothesis’ recently replaced the hygiene
hypothesis. The ‘counter regulation hypothesis’ pro-
poses that microbial infections induce regulatory
T-cell (Treg) responses, which display tolerogenic
activities and therefore inhibit both Th2- and Th1-
mediated immunopathologies.54 The reduced pres-
ence of Tregs at the feto–maternal interface after
stress exposure may represent a missing counter
regulation during pregnancy.35–37 Hence, the fetal
immune system will receive less tolerogenic
impulses after maternal stress perception. Therefore
the suppression of Tregs after stress during preg-
nancy may bridge prenatal stress with an increased
risk for atopic diseases.
The malnutrition-immune imbalance hypothesis
Maternal stress perception during pregnancy may
attack the fetal organism by inducing a prolonged
activation of the HPA-axis with an increased expres-
sion of CRH. CRH has been shown to partly medi-
ate the pyrogenic effects of the inflammatory
cytokines such as TNF-a.55 The activation of the
HPA-axis as well as the up regulation of maternal
Th1-cytokines may lead to impaired growth hor-
mone secretion, elevation of blood pressure and
reduced placental perfusion resulting in dispropor-
tionate and low birth weight and/or to a down
regulation of tolerogenic impulses in the fetal
immune system as well as a reduced concentration
of lactobacillus and bifid bacteria in the gut flora.
Therefore, maternal stress during pregnancy may
lead to a malnutrition-immune imbalance of the
growing fetus.
Further perspectives
However, stress is not just simply ‘evil’. It is very
important to precisely distinguish between negative
stress (termed distress) and positive stress
impulses (known as eustress). Therefore it might be
worthwhile to avoid distress on the one hand – or
counteract stress effects e.g. by progesterone supple-
mentation, and additionally focus on positive experi-
ences during pregnancy. A study carried out in Japan
revealed that humorous entertainment, mediated by
watching funny cartoons, significantly reduced NK
cell activity.56
The data summarized by this review clearly indi-
cate a link between maternal stress perception and
the predisposition of the child towards certain dis-
eases. The aim of this review is to foster future
research in this area with the aim to increase the
awareness of factors influencing the health status
of the next generation. Further, the precise know-
ledge of mediators and mechanism involved in
stress-triggered fetal programing of adult disease
will facilitate to introduce distinct therapeutical
interventions.
Acknowledgments
This work was supported by grants from the Charite
University Medicine. Maike Knackstedt is a research
fellow supported by the young scientist program of
the Charite.
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