Stress, glucocorticoids and liquorice in human pregnancy:Programmers of the offspring brain

K. RAIKKONEN1, J. R. SECKL2, A.-K. PESONEN1, A. SIMONS3,

& B. R. H. VAN DEN BERGH3

1Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland, 2Centre for Cardiovascular Science, The Queen’s

Medical Research Institute, University of Edinburgh, Edinburgh, UK, and 3Developmental Psychology, Tilburg University,

Tilburg, The Netherlands

(Received 18 January 2011; revised 4 April 2011; accepted 4 May 2011)

AbstractA suboptimal prenatal environment may induce permanent changes in cells, organs and physiology that alter social, emotionaland cognitive functioning, and increase the risk of cardiometabolic and mental disorders in subsequent life (“developmentalprogramming”). Although animal studies have provided a wealth of data on programming and its mechanisms, including onthe role of stress and its glucocorticoid mediators, empirical evidence of these mechanisms in humans is still scanty. We reviewthe existing human evidence on the effects of prenatal maternal stress, anxiety and depression, glucocorticoids and intake ofliquorice (which inhibits the placental barrier to maternal glucocorticoids) on offspring developmental outcomes including,for instance, alterations in psychophysiological and neurocognitive functioning and mental health. This work lays thefoundations for biomarker discovery and affords opportunities for prevention and interventions to ameliorate adverseoutcomes in humans.

Keywords: Child, glucocorticoids, human, liquorice, mood, offspring

Introduction

Mounting epidemiological evidence suggests that

smaller body size at birth and/or a shorter length of

gestation increase the risk of poorer physical health

later in life (Barker et al. 1989; Eriksson et al. 2006,

2007). The brain is particularly affected, manifesting

as altered cognitive and affective functioning and as

an increased risk of mental health disorders. These

associations may not be linear, as children born at the

upper end of the birth weight distribution may also be

at a higher risk for poorer health later in life (Gunnell

et al. 2003). These findings can be best understood

within the framework of prenatal “programming” or

developmental origins of health and disease (DOHaD;

Barker 1998). According to the DOHaD paradigm,

adverse environmental experiences during critical

periods of early development can permanently alter

or programme the structure and function of cells,

organs and physiological systems. Recent research has

shown that the influences of programming may not be

limited to the prenatal period, but may extend across

the entire human growth period from preconception

to adulthood (Barker et al. 2005). The effects of

programming are not limited to development in

childhood, but are influential across the life span

(Barker et al. 1989; Eriksson et al. 2006, 2007;

Raikkonen et al. 2007, 2008a, 2009a).

Recently, much interest has been focused on

whether developmental programming—as reflected

in alterations in body size at birth and length of

gestation—plays a role in determining individual

differences in cognitive, social and emotional func-

tioning, including characteristic traits of temperament

and personality, in neuroendocrine and autonomic

Correspondence: K. Raikkonen, Institute of Behavioural Sciences, University of Helsinki, PO Box 9, 00014 University of Helsinki, Finland.Tel: 358 9 19129501. Fax: 358 9 19129521. E-mail: katri.raikkonen@helsinki.fi

Stress, November 2011; 14(6): 590–603q Informa Healthcare USA, Inc.ISSN 1025-3890 print/ISSN 1607-8888 onlineDOI: 10.3109/10253890.2011.602147

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nervous system (ANS) functioning and in mental

health. A series of studies have shown that smaller

body size at birth and/or shorter length of gestation

associate, for instance, with alterations in hypothala-

mic–pituitary–adrenocortical (HPA) axis and ANS

functioning during daily living and under psychosocial

stress (Reynolds et al. 2001; IJzerman et al. 2003;

Wust et al. 2005; Jones et al. 2006, 2007; Phillips and

Jones 2006; Feldt et al. 2007; Kajantie et al. 2007) and

with increased risks of depression (Raikkonen et al.

2007, 2008b), suicide (Barker et al. 1995), schizo-

phrenia (Wahlbeck et al. 2001), personality disorders

(Lahti et al. 2010b), schizotypal personality traits

(Lahti et al. 2009), hostility (Raikkonen et al. 2008a),

behavioural symptoms of attention deficit/hyperactiv-

ity disorder (Lahti et al. 2006; Strang-Karlsson et al.

2008b; Heinonen et al. 2010), poorer cognitive

functioning (Gale et al. 2004; Heinonen et al. 2008;

Broekman et al. 2009; Raikkonen et al. 2009a)

internalizing and externalizing behaviour problems

(Schlotz et al. 2008), poorer sleep (Strang-Karlsson

et al. 2008a; Pesonen et al. 2009) and negative and

positive affectivity characteristics of temperament and

personality (Pesonen et al. 2006, 2008a, Schlotz et al.

2008, Schmidt et al. 2008; Lahti et al. 2010a). These

associations may not be linear as children born with

higher birth weights may display higher levels of

anxiety (Lahti et al. 2010a) and distress (Cheung

2002), and be at an increased risk for psychosis later in

life (Gunnell et al. 2003). The extent to which the

associations with higher birth weight reflect maternal

obesity, poorer health and pregnancy disorders, such

as maternal diabetes/glucose intolerance, is not clear.

In addition to the original empirical studies, several

papers exist that have reviewed the evidence linking

smaller body size at birth and/or shorter length of

gestation with psychological and psychophysiological

functioning and mental health later in life (Shenkin

et al. 2004; Gluckman et al. 2005, 2008, 2009; Seckl

and Meaney 2006; Seckl and Holmes 2007; Hanson

and Gluckman 2008; Kajantie 2008; Seckl 2008;

Raikkonen and Pesonen 2009; Kajantie and Raikko-

nen 2010).

Despite the increasing evidence pointing to the

importance of early life programming in inducing

alterations in psychological and psychophysiological

functioning and mental health, the mechanisms

through which these prenatal influences operate

remain largely unknown. Two major hypotheses have

been advanced to explain the link between events

in utero and the later risk of neuropsychiatric and

cardiometabolic disorders: maternal malnutrition and

foetal overexposure to glucocorticoid stress hormones

(Barker 1991; Edwards et al. 1993). These notions

have been extensively explored in preclinical studies.

In a range of experimental species, maternal malnu-

trition (global undernutrition or selective protein

deficiency) reduces birth weight and reliably leads to

higher blood pressure, glucose levels, altered beha-

viour and HPA axis function in adult offspring

(Warner and Ozanne 2010). Similarly, maternal stress

or administration of glucocorticoids, such as dexa-

methasone or betamethasone that freely crosses the

placenta, also reduces birth weight and produces a

similar or identical phenotype in the adult offspring

(Seckl and Holmes 2007). Similar effects occur in

non-human primates exposed to glucocorticoids in

the last half of gestation (de Vries et al. 2007). The two

hypotheses may be linked. Thus, circulating levels of

physiological glucocorticoids (cortisol and corticos-

terone) are much higher in the maternal than in the

foetal blood. This gradient is ensured by a placental

enzyme, 11b-hydroxysteroid dehydrogenase type 2

(11b-HSD2), that catalyzes the rapid inactivation of

glucocorticoids to their inert 11-keto forms (corti-

sone, 11-dehydrocorticosterone), thus forming a

physiological “barrier” to maternal glucocorticoids.

Liquorice contains compounds, such as glycyrrhizic

acid and glycyrrhetinic acid, that potently inhibit 11b-

HSDs. Maternal administration of these agents or the

derived drug carbenoxolone (Lindsay et al. 1996a,b)

or genetic knock out of the enzyme (Holmes et al.

2006) reduces birth weight and generates similar

programmed CNS and peripheral outcomes in the

adult offspring. Moreover, maternal protein malnu-

trition selectively lowers placental 11b-HSD2 (Lang-

ley-Evans et al. 1996), affording a possible link

between the proposed mechanisms. Maternal stress in

rodents also downregulates placental 11b-HSD2

(Mairesse et al. 2007), perhaps delimited by genotype

(Lucassen et al. 2009), suggesting a double hit of

elevated maternal glucocorticoids and reduced pla-

cental barrier function.

Despite this increasingly coherent body of evidence

in model organisms, understanding the key mechan-

isms of programming in humans has been much less

explored. Figure 1 outlines the mechanisms that are

potentially involved. A series of human studies have

demonstrated that prenatal environmental adversities,

such as exposure to malnutrition (Roseboom et al.

2001), maternal pre-pregnancy overweight (Rodri-

guez 2010), pregnancy disorders, such as hyperten-

sion (Tuovinen et al. 2010, 2011), tobacco (Cornelius

and Day 2009; Espy et al. 2011; Heinonen et al.

2011), cannabis (El Marroun et al. 2009) and alcohol

exposure (Hellemans et al. 2010), have the potential

to induce alterations in the offspring growth, birth

anthropometry, development and adult functions. In

this paper, we concentrate on reviewing the existing

human evidence of programming induced by prenatal

maternal stress, depression and anxiety, maternal

glucocorticoid therapy and intake of liquorice during

pregnancy.

Stress, glucocorticoids and liquorice in human pregnancy 591

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Exposure to prenatal maternal stress, depression and

anxiety: Overview of results of studies, examining offspring

behaviour with questionnaires, standardized observations,

neurocognitive tasks, EEG, MRI and fMRI

Prenatal maternal stress, depression and anxiety may

exert effects on offspring development through

multiple pathways. These pathways, which include

alterations, for instance, in maternal lifestyle, physio-

logical stress-regulatory mechanisms and placental

function, are outlined in Figure 1 and described in

more detail in previous reviews (O’Regan et al. 2001;

Seckl 2001, 2008; Seckl and Meaney 2004b; Van den

Bergh et al. 2005b; Seckl and Holmes 2007).

In humans, prospective follow-up studies have

provided accumulating evidence for an association

between prenatal exposure to high levels of maternal

stress, anxiety and depression and altered neurodeve-

lopment in the offspring at stages ranging from birth

up to 20 years of age. Importantly, these associations

persisted after controlling for postnatal maternal

Fetal genomeand epigenome

Maternalnutrition

Maternalstress

Pregnancydisorders

Placentalfunction

Fetal programming leading to life-long changes in:

Organ structureand function- Muscle tissue- Fat tissue- Pancreas- Liver- Brain

Hormonalfunction/axes - HPAA- Thyroid

Autonomicnervoussystem

Neurotransmittersystems

Glucose metabolismBody compositionLipid metabolismInsulin sensitivity

Stress responsiveness

Other factors(e.g., hormonal,growth factors)

Nutrient andoxygen

availability

Sympathoadrenalfunction

Glucocorticoidexposure

HPAA andAutonomic

nervous systemfunction

Physical health, e.g.,CHD

StrokeType 2 diabetes

Mental health Other stress-related bodily

disorders

Other healthoutcomes

- Social, emotional, cognitive functioning- Temperemant- Personality- Behavior

Figure 1. Mechanisms involved in the offspring programming. (Modified from Raikkonen et al. 2008b).

K. Raikkonen et al.592

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mood and/or other potentially important pre- and

postnatal confounders, such as alcohol consumption

and smoking, during pregnancy, birth weight and

socio-economic status, and in some studies also use of

medication, such as antidepressants, have been taken

into account. Results of the studies reviewed here are

described in Table I. The studies are organized by the

age of the offspring at the final follow-up assessment.

In newborn babies, maternal prenatal stress was

associated with neurodevelopmental alterations

manifesting as less optimal scores on the Brazelton

Neonatal Assessment Scale (Brouwers et al. 2001;

Rieger et al. 2004; Hernandez-Reif et al. 2006) and on

quantitative neurological examination (Lou et al.

1994). The newborn babies also displayed higher

cardiac vagal tone, lower Apgar score (Ponirakis et al.

1998), less optimal behavioural states (Van den Bergh

1990, 1992) and higher cortisol levels 1 week

postpartum (Diego et al. 2004). In the study of

Harvison et al. (2009), neonates of mothers scoring

lower on perinatal anxiety displayed more negative

frontal slow wave amplitudes in response to their

mother’s voice compared to a female stranger’s voice,

while neonates of mothers scoring higher on perinatal

anxiety showed the opposite pattern. The latter results

indicate that maternal anxiety may induce neurophy-

siologically based differences in attentional allocation,

processes known to be crucial to an infant’s ability to

maintain homoeostasis.

Infants of mothers scoring higher on prenatal stress

were rated by an observer as having poorer inter-

actions with their mother (Field et al. 1985), being

more irritable (DiPietro et al. 2008) and reactive

(Davis et al. 2004, 2007), having problems with

regulation of attention (Huizink et al. 2002, 2003) and

having poorer language abilities and a lower IQ

(Laplante et al. 2004, 2008). Their mothers rated

them as having more sleeping, feeding and activity

problems (Van den Bergh 1990, 1992), and being

more irritable, difficult and showing more negative

affectivity characteristics of temperament (Vaughn

et al. 1987; Van den Bergh 1990, 1992; Huizink et al.

2002, 2003; Austin et al. 2005; Pesonen et al. 2005;

McGrath et al. 2008; Henrichs et al. 2009) and crying

more excessively (van der Wal et al. 2007). Scores on

the Bayley Scales of Infant Development were worse at

8 and 24 months (Brouwers et al. 2001; Huizink et al.

2002, 2003; Laplante et al. 2004), but not in another

study of 7-month-old infants (Van den Bergh 1990,

1992). Methodological differences, such as differ-

ences in sample size and variables that were used as

covariates, may explain the conflicting findings

between the studies using the Bayley Scales. Dawson

and colleagues found that during mother–infant

interaction, children of depressed mothers showed

higher than normal heart rates and higher levels of

cortisol, and reduced activity in brain regions that

mediate positive approach behaviour. The authors

indicate that there is suggestive evidence from their

follow-up study that the postnatal experience with the

mother may have had more effect on infant frontal

EEG than on prenatal factors (Dawson and Ashman

2000; Dawson et al. 2001).

Pre-school children and children were rated by their

mothers (Martin et al. 1999; O’Connor et al. 2002,

2003; Niederhofer and Reiter 2004; Van den Bergh

and Marcoen 2004), teachers (Niederhofer and Reiter

2004; Rodriguez and Bohlin 2005), an external

observer (Van den Bergh and Marcoen 2004) or

themselves (Van den Bergh and Marcoen 2004) as

showing poorer attention, hyperactivity, behavioural

and emotional problems, and they were rated by their

teacher as having lower school grades and problem

behaviour (Niederhofer and Reiter 2004). O’Connor

et al. (2002) found that the effects of antenatal anxiety

were stronger than the effects of antenatal depression.

Finally, the results of Obel et al. (2003)indicated that

stressful life events in the mother during pregnancy

increased the risk for ADHD problems in pre-

adolescence between ages, 9–11 years.

Adolescents showed problems with cognitive control

when performing computerized cognitive tasks

measuring prefrontal cortex functioning and scored

lower on intelligence subtests at the age of 14–15 and

17 years (Mennes et al. 2006; Van den Bergh et al.

2005a, 2006). Girls displayed higher levels of

depressive symptoms (Van den Bergh et al. 2008).

Mennes et al. (2009) showed that 17-year-old

children of mothers who were more anxious between

12 and 22 weeks of gestation displayed changes in

event-related potentials (ERP) measured with EEG,

when performing a gambling task, requiring endogen-

ous control. Functional magnetic resonance (fMRI)

measures revealed that in the 20-year-old offspring,

differences related to the level of antenatal maternal

anxiety were found in the activation patterns of several

important prefrontal regions (Mennes 2008). Buss

et al. (2009) showed in a MRI study that high

pregnancy-specific anxiety in mid gestation, but not

later, is associated with decreased grey matter density

in specific brain areas, in 8-year-old children.

Some evidence also suggests that the major life

events inducing severe prenatal stress, such as death of

a close relative during pregnancy, may be associated

with stillbirth (Wisborg et al. 2008), low birth weight

and smallness for gestational age status (Khashan et al.

2008b), cerebral palsy (Li et al. 2009b) and

schizophrenia (Khashan et al. 2008a) in the offspring.

One study has linked such events also with the risk of

autism in the offspring (Kinney et al. 2008), but

another study failed to replicate this association (Li

et al. 2009a).

In humans, birth anthropometry associates with

subsequent HPA axis function. Higher plasma and

urinary glucocorticoid levels are found in children and

adults who were of lower birth weight (Clark et al.

Stress, glucocorticoids and liquorice in human pregnancy 593

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Table

I.S

tud

ies

test

ing

ass

oci

ati

on

sbet

wee

npre

nata

lm

ate

rnal

stre

ss,

an

xie

tyan

dd

epre

ssio

nw

ith

off

spri

ng

dev

elopm

ent.

Age

of

child

Mea

sure

or

type

of

pre

nata

lex

posu

re

Pre

nata

lti

min

g

wee

ks

ges

tati

on

Ou

tcom

em

easu

re(s

)R

efer

ence

(s)

2–

3d

ays

An

xie

ty(s

tate

&tr

ait

);S

tres

s(P

SS

)20;

30

NB

AS

:habit

uati

on

,so

cial

inte

ract

ion

,m

oto

r

syst

em,

state

org

an

izati

on

,st

ate

regu

lati

on

,

au

ton

om

icsy

stem

Her

nan

dez

-Rei

fet

al.

(2008)

3–

5d

ays

Tota

ld

istr

ess

,20;

30

–34

Reg

ula

tion

pro

ble

ms

(NB

AS

)R

ieger

etal.

(2004)

1w

eek

Per

inata

ld

epre

ssio

n26

Cort

isol

leve

lD

iego

etal.

(2004)

Neo

nate

An

xie

ty(g

ener

al)

40*

Au

dit

ory

evoked

resp

on

ses

(AE

R)

Harv

ison

etal.

(2009)

12

day

sD

epre

ssio

nN

ot

rep

ort

edA

tten

tiven

ess

(NB

AS

)H

ern

an

dez

-Rei

fet

al.

(2006)

4–

14

day

sL

ife

even

tsst

ress

Mid

ges

tati

on

Bir

thw

eight,

hea

dci

rcu

mfe

ren

ce,

Pre

chtl

’s

neu

rolo

gic

al

obse

rvati

on

Lou

etal.

(1994)

Bir

th,

1d

ay,

3–

4w

eeks

An

xie

ty(s

tate

an

dtr

ait

)#

16;

32

–34

Med

ical

reco

rds

(e.g

.A

pgar

scale

),ca

rdia

c

vagal

ton

e(E

KG

Porg

es’

met

hod

)

Pon

irakis

etal.

(1998)

6w

eeks

Foet

al

react

ivit

yto

mate

rnal

stim

ula

tion

(vie

win

gof

vid

eo)

32

Infa

nt

neg

ati

vere

act

ivit

yd

uri

ng

a

stan

dard

ized

lab

pro

ced

ure

DiP

ietr

oet

al.

(2008)

3m

on

ths

Dep

ress

ion

15

–28;

29

–40

Infa

nt

cort

isol

leve

lp

rean

dp

ost

infa

nt

stre

ss

test

Ober

lan

der

etal.

(2008)

4m

on

ths

An

xie

ty(s

tate

)an

dd

epre

ssio

n32

Beh

avio

ura

lre

act

ivit

y(H

IBR

P)

Dav

iset

al.

(2004)

2,

6m

on

ths

Dep

ress

ion

Th

ird

trim

este

rT

emp

eram

ent

rati

ngs

McG

rath

etal.

(2008)

3–

5m

on

ths

Str

ess

an

dd

epre

ssio

n28

–40

Face

-to-f

ace

pla

yin

tera

ctio

ns

(CC

TI)

Fie

ldet

al.

(1985)

3–

6m

on

ths

Dep

ress

ive

sym

pto

ms,

an

xie

ty

(pre

gn

an

cy-s

pec

ific)

,pare

nti

ng

stre

ss;

job

stra

in

7–

40

Exce

ssiv

ecr

yin

gva

nd

erW

al

etal.

(2007)

4–

6m

on

ths

An

xie

ty(t

rait

);d

epre

ssio

n,

life

even

tsst

ress

Thir

dtr

imes

ter

(32)

Dif

ficu

ltte

mper

am

ent

(SIT

Q)

Au

stin

etal.

(2005)

6m

on

ths

Dep

ress

ion

an

dan

xie

ty26

Infa

nt

cort

isol

leve

lpre

an

dpost

infa

nt

stre

ss

test

Bre

nn

an

etal.

(2008)

6m

on

ths

Str

ess

exper

ien

ce1st

wee

kpost

part

um

Tem

per

am

ent

(IB

Q);

neg

ati

ve

an

dover

all

tem

per

am

enta

lre

act

ivit

y

Pes

on

enet

al.

(2005)

6m

on

ths

An

xie

ty(p

regn

an

cy-s

pec

ific;

gen

eral)

12;

20

Tem

per

am

ent

(IB

Q-R

);in

fan

td

iffi

cult

ies

Hen

rich

set

al.

(2009)

1w

eek,

12

wee

ks,

7m

on

ths

An

xie

ty(s

tate

an

dtr

ait

)12

–22;

23

–31;

32

–40

Pre

chtl

’sn

euro

logic

al

obse

rvati

on

,b

eha-

vio

ura

lst

ate

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serv

ati

on

,fe

edin

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ore

,

moth

er–

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ctio

n(I

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)

Van

den

Ber

gh

,(1

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992)

7m

on

ths

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ty36

–39*

Cort

isol

leve

lof

the

child

,p

rean

dp

ost

still

face

pro

ced

ure

Gra

nt

etal.

(2009)

4–

8m

on

ths

An

xie

ty(t

rait

)21;

26

–34,

35

Tem

per

am

ent

(IT

Q-r

evis

ed)

Vau

gh

net

al.

(1987)

8m

on

ths

Daily

hass

les

15

–17,

27

–28,

37

–38

Men

tal

dev

elopm

ent

(BS

ID-M

DI)

Hu

izin

ket

al.

(2002,

2003)

9m

on

ths

9/1

1N

ot

rep

ort

edT

emp

eram

ent

(IB

Q)

Bra

nd

etal.

(2006)

9m

on

ths

9/1

128

–40

Cort

isol

leve

lof

the

child

Yeh

ud

aet

al.

(2005)

1.5

yea

rsL

ife

even

tsst

ress

(i.e

.re

lati

on

ship

pro

ble

ms)

14

mon

ths

post

part

um

*C

ogn

itiv

ed

evel

opm

ent

(BS

ID-M

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,fe

ar

react

ivit

y(L

ab

-TA

B)

Ber

gm

an

etal.

(2007)

2yea

rsA

nxie

ty(g

ener

al:

PO

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dS

TA

I),st

ress

(DS

I,

PS

S);

dep

ress

ion

(PO

MS

,C

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-D);

pre

gn

an

cy-s

pec

ific

stre

ss(P

ES

)

24,

28,

32

BS

ID:

MD

I,P

DI;

IBR

Dip

ietr

oet

al.

(2006)

3w

eeks;

1yea

r;2

yea

rsA

nxie

ty(s

tate

an

dtr

ait

)32

Ori

enta

tion

(NB

AS

),C

ogn

itiv

ed

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opm

ent

(BS

ID-M

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,T

ask

ori

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tion

an

dm

oto

r

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rdin

ati

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K. Raikkonen et al.594

Stre

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ve.

Stress, glucocorticoids and liquorice in human pregnancy 595

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1996; Phillips et al. 1998). Cortisol responses to

ACTH stimulation are exaggerated in those of low

birth weight (Levitt et al. 2000; Reynolds et al. 2001,

2007). This occurs in myriad populations (Phillips

et al. 2000; Kajantie and Raikkonen 2010) and

precedes overt adult disease (Levitt et al. 2000). It is

well known that psychological stress causes activation

of the HPA axis with a consequent elevation in the

levels of cortisol. Elevated levels of cortisol are also

among the most consistently demonstrated biological

abnormalities found in depression (Knorr et al. 2010),

and in some contexts in anxiety (Roelofs et al. 2009).

As maternal and foetal levels of cortisol are correlated

(Gitau et al. 1998; O’Keane et al. 2011), the

experience of stress and higher levels of depression

and anxiety during pregnancy may directly result in

higher foetal exposure to maternal cortisol. In a recent

study, Sarkar et al. (2008) demonstrated that the

correlation between amniotic fluid cortisol (reflecting

foetal exposure) and maternal plasma cortisol

becomes stronger the higher with levels of maternal

prenatal anxiety, while maternal prenatal anxiety

correlated with higher plasma cortisol levels of the

mother, it was not directly related to amniotic fluid

cortisol (Glover et al. 2009).

As a consequence of this biology, a number of

studies have explored the effects of maternal

psychopathology on offspring HPA axis function,

mainly observing the effects by comparing the

offspring of high vs. low anxiety, stressed or depressed

pregnant women (Glover et al. 2010). Prenatal

maternal anxiety and depression are in general

associated with raised cortisol in the offspring, but

infants of mothers exposed to the trauma of 9/11 who

themselves developed symptoms of posttraumatic

stress disorder (PTSD) had lower cortisol levels,

though this is a common finding in PTSD (Yehuda

et al. 2005). One study has provided evidence that an

altered cortisol diurnal profile in the offspring

associated with prenatal maternal anxiety was also

associated with an altered behavioural phenotype, i.e.

with depressed mood (Van den Bergh et al. 2008).

Differences have been reported throughout the

lifespan from infancy, ages 1 week to 9 months

(Diego et al. 2004; Yehuda et al. 2005; Brennan et al.

2008; Oberlander et al. 2008; Grant et al. 2009),

4–15 years of age (Gutteling et al. 2004, 2005;

O’Connor et al. 2005; Huizink et al. 2008; Van den

Bergh et al. 2008) and in adults (Entringer et al.

2009). These data suggest that, as in animal models,

the HPA axis is a prime target for prenatal influences

and programming.

The studies on prenatal maternal stress, anxiety and

depression, even when controlling for postnatal

maternal stress, anxiety and depression, cannot

overrule a possibility that a shared genetic basis may

underlie the associations with offspring neurodevelop-

mental outcomes. Most evidence pointing to a

hereditary component comes from the studies of

depression (Belmaker and Agam 2008). It is, however,

unlikely that individual differences in offspring

neurodevelopmental outcomes could be attributed

to a single genetic, epigenetic or pre- or postnatal

environmental factor. Multiple mechanisms do exist

(see Figure 1), and these may act in concert. Further

studies on the exact underlying mechanisms through

which maternal stress, depression and anxiety induce

programming of the offspring are clearly warranted.

Maternal glucocorticoid therapy

In humans, therapeutic treatment with synthetic

glucocorticoids is common in women at risk of

preterm delivery, serving to accelerate foetal lung

maturation and thus reduce neonatal morbidity and

mortality (Seckl and Meaney 2004a). The long-term

effects of this treatment are not fully determined,

although there are suggestions that foetal growth and

subsequent development may be impaired (for a

review see Bolt et al. 2001). Glucocorticoid treatment

during pregnancy typically reduces birth weight (for a

review see Sloboda et al. 2005), but long-term follow

up studies are few. Antenatal glucocorticoid admin-

istration has been linked with higher blood pressure in

adolescence (Doyle et al. 2000) and higher insulin

levels in adulthood (Dalziel et al. 2005). Studies

aimed at establishing the long-term neurological and

developmental effects of antenatal glucocorticoid

therapy are complicated by the frequency of neuro-

logical sequelae common in such children anyway.

However, in a group of 6-year-old children, antenatal

glucocorticoid exposure is associated with subtle

effects on neurological function, including reduced

visual closure and visual memory (MacArthur et al.

1982). Multiple doses of antenatal glucocorticoids

given to women at risk of preterm delivery reduced

birth weight and head circumference in the offspring

(French et al. 1999). There are also effects on

behaviour: three or more courses of glucocorticoids

associate with an increased risk of externalizing

behaviour problems, distractibility and inattention

(Yeh et al. 2004), and children exposed to a longer

(.24 h to delivery) relative to a shorter duration

(,24 h to delivery) of a single, repeat dose of

betamethasone were rated by their mothers as more

impulsive at the age of 3 years (Pesonen et al. 2009a).

Children exposed to dexamethasone in early preg-

nancy because of risk of congenital adrenal hyperpla-

sia and born at term showed increased emotionality,

unsociability, avoidance and behavioural problems

(Trautman et al. 1995). Postnatally, dexamethasone

in premature babies lowers later IQ and other higher

brain functions (Yeh et al. 2004). Overall, whilst far

from complete, evidence indicates that exposure of the

foetus (or premature neonate) to excess glucocorti-

coids that readily cross the placental and foetal tissue

K. Raikkonen et al.596

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barriers to physiological cortisol (because they are

poor substrates for 11b-HSD2) may induce altera-

tions in the developing CNS.

Maternal intake of liquorice

If glucocorticoid exposure underpins some develop-

mental effects on the foetus, what does 11b-HSD2

do? Rare children homozygous for deleterious

mutations of the HSD11B2 gene encoding 11b-

HSD2 are of substantially lower birth weight than

their siblings, many of whom will be heterozygous for

the mutations (Dave-Sharma et al. 1998). In humans,

as in rodents (Benediktsson et al. 1993), placental

11b-HSD2 activity correlates with birth weight in

some (Stewart et al. 1995), but not all studies

(Rogerson et al. 1997). However, such correlations

are weak and mechanisms can only be inferred.

A handful of recent studies have focused on prenatal

maternal intake of liquorice confectionery as a natural

experimental platform to address mechanisms of

programming. These have been conducted in Finland

where consumption of large quantities of liquorice

confectionery is common among young women:

nearly half of the pregnant women consume at least

some liquorice (Raikkonen et al. 2009b; Strandberg

et al. 2001). Glycyrrhizin (3b-D-diglucuronyl-18b-

glycyrrhetinic or -glycyrrhizic acid) is a natural

constituent of liquorice. Its hemisuccinate synthetic

analogue, carbenoxolone, was a clinical drug formerly

used to treat peptic ulcers. Its water solubility makes it

attractive for use in preclinical and human studies

(Welberg et al. 2000). These agents are potent (low

nanomolar Ki) inhibitors of 11b-HSD2. Though they

also potently inhibit 11b-HSD type 1, this is little

expressed in the foetus at least in rodents (Speirs et al.

2004). In normal circumstances, this placental

enzyme metabolizes up to 80–90% of maternal active

cortisol to inactive cortisone, a function inhibited by

carbenoxolone, at least in intact placenta ex vivo

(Benediktsson et al. 1997).

In 1998, a project was initiated to test whether

varying levels of maternal consumption of glycyrrhizin

in liquorice during pregnancy was associated

with body size at birth and length of gestation. In

over 1000 pregnant women, prenatal exposure to high

(.500 mg/wk) compared to zero-low (0–249 mg/wk)

or moderate (250–499 mg/wk) glycyrrhizin in

liquorice was associated with a slightly shorter

duration of gestation (Strandberg et al. 2001).

Glycyrrhizin intake during pregnancy was not

significantly associated with birth anthropometry.

The findings on shorter length of gestation were

replicated in another Finnish cohort: high intake of

glycyrrhizin during pregnancy was associated with

over a twofold increased risk in the rate of preterm

delivery (Strandberg et al. 2002).

In a follow-up study, the long-term effects of

maternal intake of liquorice during gestation on

8-year-old offspring psychological development,

mental health and psychophysiological functioning

were determined. In comparison to the group whose

mothers had zero-low glycyrrhizin exposure, those

with high exposure scored significantly lower on verbal

and visuo-spatial abilities and in narrative memory. In

addition, children in the high-exposure group had

significant 2.4–3.0-fold increased risk of externalizing

symptoms, attention, rule breaking, aggression pro-

blems and DSM IV-based symptoms of obsessive

defiant disorder (Raikkonen et al. 2009b). The effects

on cognitive performance appeared dose-related.

None of the associations were affected by birth weight

or duration of gestation and other pre- and perinatal,

maternal and child characteristics implicated as risks

for pregnancy and/or cognitive and psychiatric

outcomes.

The HPA axis of these children was also affected.

Children of mothers consuming high levels of

glycyrrhizin had a higher salivary cortisol peak and

area under the curve upon awakening and higher

overall salivary cortisol throughout a Trier Social

Stress Test for Children (TSST-C; Raikkonen et al.

2010c). The associations with salivary cortisol peak

and salivary cortisol baseline during the TSST-C were

dose-related. As far as could be ascertained, the results

were not due to confounding factors such as maternal

health during pregnancy, including blood pressure

levels, obesity and pregnancy disorders, birth anthro-

pometry and length of gestation, maternal social class

at birth and in a follow-up at the child’s age of 8 years,

maternal smoking and alcohol consumption during

pregnancy, and child characteristics, such as sex,

growth in height, head circumference and difficulties

in cognitive functioning that might interfere with

cognitive performance, associate with psychiatric

symptomatology, and alter performance in the

TSST-C. We have previously reported, in this

same sample of 8-year-old children, that shorter

sleep duration and lower sleep efficiency (percent time

spent asleep whilst in bed) are associated with

alterations in the diurnal salivary cortisol pattern and

in salivary cortisol responses during the TSST-C

(Raikkonen et al. 2010b). Poorer sleep may thus

introduce another factor that may confound the

associations between liquorice consumption and

HPA axis activity. Maternal intake of liquorice during

pregnancy is, however, not associated with the

children’s sleep patterns (Raikkonen, unpublished

data). Thus, when we further controlled the associ-

ations of maternal liquorice intake during pregnancy

and their children’s HPA axis function for the

children’s sleep duration and sleep efficiency, the

associations remained identical.

These findings suggest that high maternal liquorice

consumption during pregnancy may exert deleterious

Stress, glucocorticoids and liquorice in human pregnancy 597

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effects upon cognitive and psychiatric outcomes and

HPAA functioning in children paralleling the effects

seen in preclinical models. Whilst it remains to be

ascertained whether the dose of liquorice consumed

affects placental 11b-HSD2 function appreciably

in vivo (mice lacking one copy of the gene encoding

11b-HSD2 have intermediate reductions in birth

weight), it is plausible to suggest that this may occur

and that placental glucocorticoid “leakiness” may

have an impact on foetal brain development during

periods critical for affective and cognitive develop-

ment with persisting impacts. If humans resemble

rodents, then maternal stress-related disorders may

further lower placental glucocorticoid barrier

function.

Conclusion

This review shows, first, that accumulating evidence

exists suggesting that maternal negative emotions

during pregnancy are linked with the long-term

behaviour and physiology of her child, even after

controlling for relevant covariates. The range of

maternal “stressors” that predict the child outcomes

is quite wide. Moreover, a wide range of different

outcomes have been found to be affected by these

maternal stressors (Glover et al. 2010). This should

come as no surprise. In terms of mechanisms, we are

far from understanding how and when the early

hormonal environment may affect the refinement of

neural circuits in specific brain layers and areas which

will later determine the way in which sensory-

cognitive, motor, arousal and emotional structure–

function relationships are affected (Van den Bergh

et al. 2005a; Fox et al. 2010).

Second, this review shows that there are links

between prenatal maternal intake of glucocorticoids

and of liquorice confectionery and long-term beha-

viour and physiology of her child, even after

controlling for relevant covariates. These findings

may not generalize merely to intake of liquorice

confectionery.

Because of its sweetening (50–200 times sweeter

than refined sugar) and flavouring capacity, glycyr-

rhizin is also used as a natural sweetener and is also

found in other foodstuffs, including some candies and

chewing gum, herbal teas, alcoholic and non-alcoholic

drinks, tobacco and some traditional (e.g. cough

medicine) as well as some herbal medicine (to treat

stomach ulcers, sore throat and viral infections).

Hence, not surprisingly, according to some estimates

the daily consumption levels of glycyrrhizin range

from 1.6 to 215.2 mg (Isbrucker and Burdock 2006).

This estimate was derived from the USA where

consumption of liquorice confectionery is not popular.

Glycyrrhizin is generally recognized as safe for use

in foods, though the European Community’s

Scientific Committee on Food and the FAO/WHO

Expert Committee (http://ec.europa.eu/food/fs/sc/scf/

out186_en.pdf) have considered that a consumption

of 100 mg/day may be a reasonable upper limit for the

majority of the population, and the FDA recommends

that if glycyrrhizin-containing foods are not consumed

in excess or by sensitive individuals, these foods do not

pose a health hazard (http://www.accessdata.fda.gov/

scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr ¼ 184.

1408). The findings reviewed here suggest that

consumption of large quantities of glycyrrhizin in

foodstuffs may alter offspring’s brain development and

subsequent function, and therefore, it may be prudent

to inform pregnant women of the potential hazards of

eating large quantities of liquorice.

Future studies should try to increase knowledge

about mechanisms underlying the effect of prenatal

influences on social-emotional, cognitive and beha-

vioural problems, particularly about whether prenatal

stress and gene-environment interactions affecting the

HPA-axis play a role in early developmental processes.

It has become increasingly clear that epigenetic

changes, including DNA methylation and histone

modifications, are causally involved in a range of

developmental processes by affecting transcriptional

activity. For the future, it is important that these

epigenetic processes, that take place also in the

placenta, are integrated in the studies of prenatal

stress. They provide “a physical basis for the influence

of the perinatal environmental signals over the life of

the individual” (Meaney 2010). Moreover, the

eventual moderating influence of other environmental

factors, such as the postnatal caregiving environment,

should also be studied. There is evidence that severe

early life stress may carry consequences on a wide

range of developmental outcomes, including physical

and mental health, psychophysiological functioning

and cognitive abilities and attained social class in

adulthood (Pesonen et al. 2007, 2008b, 2010, 2011;

Alastalo et al. 2009; Raikkonen et al. 2011). Whether

the postnatal environmental influences buffer or add

to the prenatal influences is little studied. Results of

these research efforts would open the way for the

development of targeted pre- and perinatal prevention

and intervention strategies that could reduce the risk

that prenatal environmental adversities carry for early

functioning and later mental health of children, and

have significant consequences for the long-term health

and well-being of the children.

Declaration of interest: This work was sponsored by

the grants from the European Science Foundation,

Stress and Mental Health programme (EuroS-

TRESS), the Finnish Academy, the Medical Research

Council (UK), The Netherlands Organisation for

Scientific Research (NWO). The authors report no

conflicts of interest. The authors alone are responsible

for the content and writing of the paper.

K. Raikkonen et al.598

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