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


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.


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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Mothers in Stress: Consequences for the Offspring

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