Antenatal maternal stress and long-term effects on child ...

Antenatal maternal stress and long-term effectson child neurodevelopment: how and why?

Nicole M. Talge,1,4 Charles Neal,2,4 Vivette Glover,3,4 and the Early Stress,Translational Research and Prevention Science Network: Fetal and Neonatal

Experience on Child and Adolescent Mental Health1Institute of Child Development, University of Minnesota, USA; 2Pacific Research Center for Early HumanDevelopment, University of Hawaii John A. Burns School of Medicine, USA; 3Institute of Reproductive and

Developmental Biology, Imperial College London, UK; 4The Early Stress, Translational Research and PreventionScience Network: Fetal and Neonatal Experience on Child and Adolescent Mental Health, USA

We review a significant body of evidence from independent prospective studies that if a mother isstressed while pregnant, her child is substantially more likely to have emotional or cognitive problems,including an increased risk of attentional deficit/hyperactivity, anxiety, and language delay. Thesefindings are independent of effects due to maternal postnatal depression and anxiety. We still do notknow what forms of anxiety or stress are most detrimental, but research suggests that the relationshipwith the partner can be important in this respect. The magnitude of these effects is clinically significant,as the attributable load of emotional/behavioral problems due to antenatal stress and/or anxiety isapproximately 15%. Animal models suggest that activity of the stress-responsive hypothalamic-pituit-ary-adrenal (HPA) axis and its hormonal end-product cortisol are involved in these effects in bothmother and offspring. The fetal environment can be altered if stress in the mother changes her hormonalprofile, and in humans, there is a strong correlation between maternal and fetal cortisol levels. However,many problems remain in understanding the mechanisms involved in this interaction. For example,maternal cortisol responses to stress decline over the course of pregnancy, and earlier in pregnancy, thelink between maternal and fetal cortisol is less robust. It is possible that the effects of maternal anxietyand stress on the developing fetus and child are moderated by other factors such as a maternal diet(e.g., protein load). It is suggested that extra vigilance or anxiety, readily distracted attention, or a hyper-responsive HPA axis may have been adaptive in a stressful environment during evolution, but existstoday at the cost of vulnerability to neurodevelopmental disorders. Keywords: Antenatal, prenatal,stress, anxiety, child neurodevelopment, attention deficit/hyperactivity, HPA axis, cortisol. Abbrevia-tions: HPA: hypothalamic-pituitary-adrenal; PVN: paraventricular nucleus of the hypothalamus; CRH:corticotropin releasing hormone; ACTH: adrenocorticotropin; GR: glucocorticoid receptor; MR: miner-alocorticoid receptor; 11bHSD-2: 11 beta hydroxysteroid dehydrogenase-2; NBAS: Neonatal BehavioralAssessment Scale; ADHD: attention deficit hyperactivity disorder; MDI: Bayley Mental DevelopmentIndex; PDI: Bayley Physical Development Index.

The enduring effects of events experienced duringhuman prenatal development have long been known,perhaps best illustrated by the effects of teratogenson postnatal physical, cognitive, and social out-comes. Prenatal exposure to toxic agents, such asalcohol, radiation, environmental pollution, andmaternal infections, can lead to a range of adversedevelopmental outcomes. The nature and severity ofsome of these effects appear to be influenced by thedegree and timing of the exposure during gestation.For example, during an outbreak of German measles(rubella) in the mid-1960s, as many as 20,000 ba-bies were born with significant birth defects in theUnited States (Eberhart-Phillips, Frederick, & Bar-on, 1993). Babies whose mothers were exposedduring their first trimester, a period of generalizedand rapid organ development, tended to displaywidespread, global effects including cognitive dys-function, heart malformations, cataracts, and deaf-ness, as well as genital and intestinal abnormalities.

In comparison, babies whose mothers were exposedduring the second and third trimesters, periods oforgan system refinement and somatic growth,tended to have low birth weights, experience hearingloss, and display skeletal abnormalities. Suchobservations strongly support the notion that pre-natal development is characterized by sensitiveperiods, developmental windows when organismsare particularly vulnerable to the relatively persist-ent and unmodifiable effects of environmental eventsor stressors. The specific structures and systemsvulnerable at any given point in time appear to bethose undergoing rapid maturational change.

More recently, the concept of sensitive periods inrelation to human prenatal development has beeninvoked to describe the fetal origins of adult disease,an idea since termed the ‘Barker hypothesis’. Barkerstated that ‘Coronary heart disease, Type 2 diabetes,stroke and hypertension originate in developmentalplasticity, in response to undernutrition during fetallife’ (Barker et al., 1993). Indeed, lower birth weights(even those occurring within the normal range) haveConflict of interest statement: No conflicts declared.

Journal of Child Psychology and Psychiatry 48:3/4 (2007), pp 245–261 doi:10.1111/j.1469-7610.2006.01714.x

� 2007 The AuthorsJournal compilation � 2007 Association for Child and Adolescent Mental Health.Published by Blackwell Publishing, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main Street, Malden, MA 02148, USA

been shown to place individuals at risk for develop-ing features of cardiovascular disease and metabolicdisorders such as diabetes, in adulthood (Barker,2002, 2004, 2005; Barker & Hanson, 2004). Mor-tality rates associated with these conditions similarlyincrease among individuals with lower birth weightsand smaller neonatal head circumferences (Barker,Bull, Osmond, & Simmons, 1990). These relationsremain significant even when potential confoundingfactors such as diet and socioeconomic status aretaken into account. It has become clear that neo-natal outcomes are often markers for future health,and these findings have stimulated many lines ofresearch to explore the nature of fetal programming.

Fetal programming is a concept that describes thefetus’ physiological adaptation to the characteristicsof the intrauterine environment within which it isdeveloping. Such adaptation may subsequentlyaffect the set points of physiological systems of thebody undergoing rapid structural and functionalchanges, including those that maintain homeo-stasis. If not optimally suited for the postnatalenvironment, the prenatal physiological adaptationsmay render the offspring vulnerable to the develop-ment of health problems later in life. For example,offspring of nutrient-restricted pregnant dams haveatypically high percentages of body fat and weight at9 months of age if they are allowed to feed ad libitum

postnatally (Desai, Gayle, Babu, & Ross, 2005).However, when nutrient restriction continues intothe postnatal months, body fat and weight at9 months are typical and no different in comparisonto offspring who were not nutritionally restrictedduring either the prenatal or postnatal periods.Although fetal programming has been primarilydiscussed in relation to negative outcomes, patho-logy is not inherent in this concept (Schwartz &Morrison, 2005). Prenatal programming effects,according to this perspective, are aspects of onto-logical development.

The aim of this paper is to review evidence for theeffects of antenatal maternal psychosocial stress onchild neurodevelopmental outcomes and discusssome possible mechanisms for these effects. In thereview of human studies that follows (see Table 1),prenatal stress is often inferred from maternalexposure to traumatic events, the presence of mooddisorder symptomatology, or self-reports of dailyhassles and negative life events during pregnancy.The findings will be discussed with respect to the ageat which postnatal outcomes were assessed, in orderto discern the extent to which this prenatal experi-ence persists into postnatal life.

Developmental consequences of prenatalstress on human behavior

Symptoms of anxiety and depression occur fre-quently during pregnancy. Indeed, they are more

common in late pregnancy than in the postpartumperiod (Heron, O’Connor, Evans, Golding, & Glover,2004). As early as 400 B.C., Hippocrates was awareof the importance of emotions in influencing preg-nancy outcomes. Additionally, more than a thou-sand years ago in China, awareness of theimportance of prenatal attitudes led to the institu-tion of the first antenatal clinic (Ferreira, 1965).However, it is only relatively recently that thisidea has been substantiated by human behavioralresearch.

Neonatal outcomes

In general, studies point to a small, but reliable linkbetween prenatal stress and pregnancy outcomes inhumans. Maternal reports of daily hassles as well asdepression and anxiety symptoms appear to be as-sociated with both earlier delivery and smaller size atbirth, which in turn, are risk factors for impairedcognitive and social developmental outcomes(Wadhwa, 2005; Wadhwa, Sandman, & Garite,2001; Rini, Dunkel-Schetter, Wadhwa, & Sandman,1999; Wadhwa, Sandman, Porto, Dunkel-Schetter,& Garite, 1993). Recent studies also suggest an as-sociation between antenatal stress and lower scoreson neonatal neurobehavioral assessments.

The relation between prenatal stress and neonataloutcomes appears to depend, in part, upon the nat-ure of the stressful experience as well as the specificoutcome under investigation. This may explain whystudies of women exposed to traumatic events, forexample, have yielded somewhat equivocal results.In one study, women who were pregnant during the6.8 magnitude Northridge, CA earthquake deliveredapproximately one week earlier than expected giventhe date of their last menstrual cycle (Glynn,Wadhwa, Dunkel-Schetter, Chicz-DeMet, & Sand-man, 2001). Infants were not born prematurely,however, because mean gestational lengths weregreater than 38 weeks. In contrast, no differences ingestational length or risk for premature labor wereobserved among expectant mothers who were pres-ent at or otherwise proximal to the World TradeCenter during the September 11 terrorist attacks(Berkowitz et al., 2003). Infants proximal to theWorld Trade Center in utero, however, were nearlytwice as likely to experience intrauterine growthrestriction, having birth weights below the 10thpercentile given their gestational age (OR ¼ 1.90).Evidence from the animal literature suggests thatthese effects may be due at least in part to elevationsin maternal cortisol concentrations, which havebeen associated with both lower birth weights andelevated glucocorticoid levels in offspring (Seckl &Meaney, 2004).

Epidemiological studies examining the effects ofdaily hassles, negative life events, and occupationalstressors during pregnancy have generally yieldedmore consistent results with respect to neonatal

246 Nicole M. Talge et al.

� 2007 The AuthorsJournal compilation � 2007 Association for Child and Adolescent Mental Health.

Table

1Effects

ofantenatalstressonneurodevelopmentaloutcomes

Stu

dy

Design

Sample

Stressor

Tim

ing*

Outcomes

Results

Neonataloutcomes

Wadhwaetal.(1993)

prospective

N¼

90upper-middle

class

life

events,dailyhassles

(SRLE,PSS,DHQ)

28and30weeks

birth

outcomes

–associatedwithlowerbirth

weightand

shortergestationallength

–controlledforbiomedicalrisk

Lou

etal.(1994)

prospective

N¼

70stressed,

N¼

50comparison

life

events

(GHQ)

mid-gestation

birth

outcomes,

neurobehaviora

ldevelopmentat

4–1

4days

–smallerheadcircumference,lowerbirth

weightandlowerPrechtl

scoresassociated

withgreaternumberoflife

events

Copperetal.(1996)

prospective

N¼

2593highrisk

depression/anxiety

symptoms(ASAPSP)

25–2

9weeks

birth

outcomes

–associatedwithincreasedriskforpreterm

birth

(OR¼

1.16)andlow

birth

weight

(OR¼

1.08)norelationobservedwithIU

GR

–controlledformatern

alage,education,

maritalstatu

s,substanceuse

Brett

etal.(1997)

retrospective

N¼

421prematu

re;

N¼

612atterm

occupationalstress

(JCS)

6mopostp

artum

gestationallength

–highstrain

(highdemand/low

control)

full-tim

ejobsassociatedwithpreterm

birth

(OR¼

1.4)

–controlledforra

ce,SES,matern

alhealth

Glynnetal.(2001)

retrospective

N¼

40

earthquake

variable

gestationallength

–reductionin

gestationallength

among

womenexperiencingth

eearthquakeduring

pregnancy,particularlyduringth

efirst

trim

ester

–controlledforobstetric

risk,matern

alCRH

levels

Berk

owitzetal(2003)

retrospective

N¼

187;nearWTC

N¼

2367comparison

Sept.

11(PTSDC)

variable

birth

outcomes

–noreductionin

gestationallength

–increased

riskofintrauterinegrowth

restriction

(OR¼

1.90)forwomennearWTC

Field

etal.(2003)

prospective

N¼

132middle-income

depression/anxiety

angersymptoms

(CES-D

;STAI;POMS)

20weeks

birth

outcomes

EEG,vagaltone

neurobehaviora

l

–highanxiety

associatedwithlowerbirth

weightandvagaltonedevelopment,

higher

rightfrontalEEG

asymmetry,poorer

perform

anceonBra

zelton

Dole

etal.(2003)

prospective

N¼

1962highrisk,

low

income

life

events,

pregnancy-specific

anxiety

(LES)

24–2

9weeks

gestationallength

–life

events

andpregnancy-specificanxiety

associatedwithincreasedriskforpreterm

birth

(OR¼

1.8

and2.1

respectively)


altobaccoandalcohol

use,bacterialvaginosis

infection

Infant&

childhoodoutcomes:social/emotional

O’Connoretal.(2002)

prospective

N¼

7448ALSPAC

depression/anxiety

symptoms

(EPDS;Crown-C

risp)

18,32weeks’

gestation;

8weeks,8,21,

33month

spostn

atal

behaviora

lproblems

–higherlevels

ofanxiety

ateithertimepoint

at47month

spredictedincreasedriskof

emotionalproblems

–boysmore

likely

todisplayhypera

ctivity/

attentionproblems

–controlledforpostn

atalanxiety,depression,

SES,parity,birth

outcomes

Davis

etal.(2004)

prospective

N¼

22low

risk

depression/anxiety

symptoms(C

ES-D

;STAI)

thirdtrim

ester

tempera

mentat

4mo

–higherlevels

ofdepressionandanxiety

predictedheightenedresponseto

novelty


ataldepression&

anxiety

Antenatal maternal stress and long-term effects on child neurodevelopment 247


Table

1(C

ontinued)

Stu

dy

Design

Sample

Stressor

Tim

ing*

Outcomes

Results

VandenBergh&

Marcoen(2004)

prospective

N¼

72low

risk

anxiety

symptoms

(STAI)

12–2

2,23–3

1,

32–4

0weeks’

gestation;8,10,

28weeks

postn

atal

behaviora

lproblemsat

8–9

years

(CBCL)

–higherlevels

ofanxiety

predictedvariationin

extern

alizingproblemsandself-reportedanxi-

ety


atalanxiety,SES,gender

VandenBerghetal.

(2005)

prospective

N¼

57low

risk

anxiety

symptoms

(STAI)

12–2

2,23–3

1,&

32–4

0weeks’

gestation;1,10,

28weeks,8/9,

14/15years

postn

atal

behaviora

lproblemsat

14–1

5years

–higher

anxiety,

particularly

betw

een

12–

22weeks’gestation,predictedhigherlevels

of

impulsivityandlowerscoresonth

eWISC


atalmatern

alanxiety

Infantandchildhoodoutcomes:cognitive

Huizinketal.(2003)

prospective

N¼

170low

risk

dailyhassles,

pregnancy-specific

anxiety

(EPL;PRAQ-R

)

15–1

7,27–2

8,&

37–3

8weeks

Bayleyscales

at3and8mo

–daily

hassles,

especially

betw

een

15–

17weeks,

predicted

lower

MDI

scores

at

8month

s–

controlled

for

postn

ataldepression,SES,

obstetric

complications

LaPlante

etal.(2004)

retrospective

N¼

58upper-middle

&upperclass

Quebecicestorm

(IES-R

;researcher-constructed

questionnaire)

variable

BayleyMDI,

MCDIat

24mo

–matern

alanxiety

predicted11%

and12%

inMDI

and

MacArthur

vocabulary

scores,

respectively

–controlled

for

postn

ataldepression,birth

outcomes,andobstetric

complications

Niederh

ofer&

Reiter

(2004)

prospective

N¼

247low

risk

psychologicaldistress

(researcher-constructed

questionnaire)

16–2

0weeks

academic

achievementat

6years

–greater

psychological

distress

associated

withlowergra

desin

school

DiPietroetal.(2006)

prospective

N¼

94low

risk

depression,anxiety

symptoms;

pregnancy-specific

anxiety

(POMS;STAI;

DSI;

PES)

24,28,or

32weeks

BayleyScales

at24mo

–higher

levels

of

anxiety

and

depression

positively

relatedto

MDIandPDIscores


aleducation,fetalsex

Bergmanetal.

(unpublished)

prospective

N¼

125

life

events

17weeks

Bayleyscales

at18mo

–greater

number

ofantenatalnegative

life

events

associatedwithlowerMDIscores

–no

association

observed

with

postn

atallife

events,matern

alage,smoking

Infant&

childhoodoutcomes:latera

lity

&oth

erneurodevelopmentaldisord

ers

Obeletal.(2003a)

prospective

N¼

824

life

events

(GHQ;

researcher-constructed

questionnaire)

8–1

9&

27–3

4weeks

handednessat

36mo

–life

events,particularly

those

betw

een

the

firstandsecondassessments,predictedhigh-

erincidenceofmixed-h

andedness

–controlledforparenthandedness

Gloveretal.(2004)

prospective

N¼

7431ALSPAC

depression/anxiety

symptoms(E

PDS;

CrownCrisp)

18,32weeks;

8weeks

postn

atal

handednessat

42month

s–antenatalanxiety,butnotdepression,pre-

dicts

increased

likelihood

ofmixed-h

anded-

ness(O

R¼

1.28)

–controlled

formatern

aldru

guse

and

age,

obstetric

complications,SES,birth

outcomes,

postn

atalanxiety

anddepression



outcomes. For instance, Dole and colleagues (2003)found that maternal perception of negative lifeevents between 24 and 29 weeks’ gestation wassignificantly related to increased risk of pretermbirth (OR ¼ 1.8). This effect was not influenced byobstetric health or maternal substance use. African-Americans displayed a higher incidence of pre-mature labor, as is well documented in the literature,but no interactions were observed between prenatalstress and maternal race. The results of this studywere corroborated by Copper et al. (1996), who usedmaternal self-reports of mood disorder symptoms asmarkers of prenatal stress. Nearly 3000 motherscompleted anxiety and depression questionnaires atapproximately 26 weeks’ gestation, at which timedemographic information and obstetric history wasalso obtained. Although maternal anxiety anddepression scores were significantly associated withlower educational levels and substance use, theyalso uniquely predicted both premature birth (OR ¼1.16) and low birth weight (OR ¼ 1.08). Occupa-tional stressors have also been associated withan increased risk of premature labor (OR ¼ 1.4),although this effect appears to be carried by womenexperiencing high job strain for at least 30 weeks oftheir pregnancy (Brett, Strogatz, & Savitz, 1997).

In addition to gestational age and weight at birth, afew studies have also explored relations betweenprenatal stress and neurobehavioral outcomes dur-ing the neonatal period. For example, Field et al.(2003) reported that newborns of mothers with highlevels of anxiety display greater right frontal brainactivation, a physiological profile that has beenassociated with the display of negative affect frominfancy to adulthood (Davidson, 1998). The infantsalso spent more time in deep sleep, less time in quietand active alert states, and showed more statechanges and less optimal performance on theNeonatal Behavioral Assessment Scale (NBAS), astandard neurobehavioral assessment of motormaturity and autonomic stability during the neo-natal period. These findings extended those of Louet al. (1994), who found that antenatal life eventspredicted lower scores on another neurodevelop-mental assessment, the Prechtl scale, as well assmaller head circumference and lower birth weight.

It is often unclear whether maternal appraisals orthe nature of the stressful experience are drivingthese effects, since self-reports were employed in thestudies that conceptualized stress as responses tochronic, day-to-day events. Definitions of prematur-ity also vary across the studies. For example, Copperet al. (1996) characterized premature birth as deliv-ery prior to 35 weeks’ gestation, while the otherstudies used a criterion of 38 weeks. Assuming thatmaternal psychological stress results in a modestreduction in gestational length, such conservativecriteria might artificially attenuate the magnitudeof the associated odds ratios. This is particularlyimportant with the recent emphasis in newbornT

able

1(C

ontinued)

Stu

dy

Design

Sample

Stressor

Tim

ing*

Outcomes

Results

Beversdorf

etal.

(2005)

retrospective

N¼

188autism

N¼

212;no

neurodev.diagnosis

life

events

(SRRS)

0–4

0weeks

incidenceof

autism

–life

events,particularlybetw

een

25–2

8weeks,wasassociatedwithincreased

incidenceofautism

Adult

outcomes

Seltenetal.(1999)

retrospective;

archival

N¼

2786exposed;

N¼

14,778

non-exposed

flood(N

eth

erlands)

variable

psychopath

ology

–offspringatincreasedriskofdeveloping

schizophrenia

(OR¼

1.8)

Watsonetal.(1999)

retrospective;

archival

N¼

611exposed;

N¼

604non-exposed

earthquake(C

hina

variable

psychopath

ology


affectivedisord

ers

VanOs&

Selten

(1998)

retrospective;

archival

N¼

419exposed;

N¼

1480non-exposed

WWII

(Neth

erlands)

variable

psychopath

ology


schizophrenia

(OR¼

1.15),particularlyif

exposedduringth

efirsttrim

ester

(OR¼

1.28)

Key:ALSPAC:AvonLongitudinalStu

dyofParents

andChildren;ASAPSP:AbbreviatedScale

forth

eAssessmentofPsychosocialStatu

sin

Pregnancy;CES-D

:CenterforEpidemiologic

Stu

diesDepressionScale;CRH:Corticotropin-R

eleasingHorm

one;DHQ:DailyHasslesQuestionnaire;DSI:DailyStressInventory;EPDS:EdinburghPostn

atalDepressionScale;EPL:

EverydayProblem

List;

GHQ:Genera

lHealthQuestionnaire;HSC:HopkinsSymptom

Checklist;

IES-R

:Im

pactofEventScale-R

evised;IU

GR:intrauterinegrowth

retard

ation;JCS:Job

ContentSurvey;LBW:Low

Birth

Weight;LES:LifeExperiencesSurvey;MCDI:MacArthurCommunicativeDevelopmentInventory

;MDI:MentalDevelopmentIndex(B

ayley);PDI:Physical

DevelopmentIndex(B

ayley);PES:PregnancyExperiencesScale;POMS:Profile

ofMoodStates;PRAQ-R

:PregnancyRelatedAnxietiesQuestionnaire-R

evised;PSS:PerceivedStressScale;

PTSDC:Posttra

umaticStressDisord

erChecklist;

SRLE:Schedule

ofRecentLifeEvents;SRRS:SocialReadjustm

entRatingScale;STAI:State-T

raitAnxiety

Inventory

forAdults;WISC:

WechslerIntelligenceScale

forChildren;WTC:WorldTra

deCenter.



medicine on physical and cognitive morbidity in thenear-term infant (born between 34 and 37 weekspostconceptional age). Additionally, because the re-sults of these studies focused exclusively on preg-nancies that led to live births, it remains unclear howprenatal stress influences the rates of spontaneousabortions.

Infant and childhood outcomes

There is now good evidence from many independentprospective studies that antenatal stress is associ-ated with adverse neurobehavioral outcomes, includ-ing social/emotional and cognitive functioningduring childhood. Despite the fact that differentmethods for measuring both antenatal stress andthe postnatal outcomes of interest were employedacross studies, the results were consistent inestablishing a prospective association betweenantenatal stress and neurobehavioral development.

Infant and childhood outcomes: social/emo-tional. With respect to social development, the out-comes receiving the most attention have beentemperament and behavior problems. The tempera-ment work represents a relatively recent area ofinvestigation and has been studied exclusively dur-ing infancy. For example, Davis et al. (2004) foundthat scores on depression and anxiety inventoriesobtained during the third trimester of pregnancypredicted 27% and 20% of the variance in infants’observed behavioral reactivity at 4 months, respect-ively. Specifically, infants of mothers reporting higherlevels of depression and anxiety during pregnancytended to display higher levels of negative affect andmotor activity when presented with a series of noveltoys. This behavioral profile in infancy, in turn, hasbeen associated with shyness and anxiety disordersin later childhood (Kagan, Reznick, & Snidman,1987). It is of note that maternal anxiety and de-pression scores did not fall within the clinical range.Additionally, postnatal measures of anxiety and de-pression were unrelated to the infant temperament. Itis not known how prenatal stress is related to otheraspects of temperament (e.g., exuberance), or theextent to which relations already demonstrated pre-dict temperament later in infancy or beyond.

In contrast, studies of antenatal stress and socialdevelopmental outcomes during childhood have fo-cused primarily on parent-reported behavioral prob-lems. Four independent prospective studies havefound associations between antenatal stress andsocial/emotional problems during childhood. Themost consistently observed adverse outcome is at-tention deficit hyperactivity disorder (ADHD) symp-toms, observed in children between 4 and 15 years ofage (O’Connor, Heron, Golding, Beveridge, & Glover,2002; Van den Bergh et al., 2005). However, othereffects have also been described, such as increasesin anxiety symptoms (O’Connor et al., 2002) and

externalizing problems (Van den Bergh & Marcoen,2004). It is of interest that in the non-human primatestudies of prenatal stress, a consistent finding in theoffspring has been deficits in attention (Schneider,Moore, Kraemer, Roberts, & DeJesus, 2002).

Infant and childhood outcomes: cognitive. Otherstudies show an effect of prenatal stress on thecognitive development of the child, as assessed byscores on the Bayley Mental Developmental Index(MDI), language development measures, or by schoolgrades. These studies are generally fewer in numberand have focused primarily on infants and youngchildren, although one study found an associationbetween maternal antenatal stress and school marksat 6 years (Niederhofer & Reiter, 2004). In one study,Huizink, Robles de Medina, Mulder, Visser, andBuitelaar (2003) examined the association betweenmaternal reports of daily hassles, pregnancy-relatedconcerns, and performance on MDI of the BayleyScales of Infant Development at 3 and 8 months ofage. Higher levels of daily hassles during early ges-tation and pregnancy-specific anxiety during mid-gestation were associated with lower scores on theMDI. However, this relation was observed only at the8-month assessment. One possible explanation forthese findings is that performance on the Bayley at8 months requires the activity of brain regions beingthat are coming ‘on-line’ during late infancy, such asthe hippocampus, and that these same brain regionsare particularly susceptible to prenatal insults.Research from the iron deficiency literature suggeststhat this is a viable hypothesis for explainingthe relation between perinatal events and postnatalsequelae (Schmidt & Georgieff, 2006). Bergman,Sarkar, O’Connor, and Glover (unpublished obser-vations) have also found that exposure to lifeevents during pregnancy was associated with asignificant reduction in MDI scores in children of14–19 months; there was no such link with post-natal life events scores.

Maternal exposure to traumatic events duringpregnancy has also been associated with children’scognitive outcomes. Toddlers whose mothers werepregnant during the 1998 ice storm in Quebec, adisaster that resulted in the loss of electricity andwater for up to five weeks in some regions of theprovince, displayed lower MDI and language develop-ment scores compared to standardized norms(LaPlante et al., 2004). Additionally, maternal sub-jective appraisals of distress during the ice stormuniquely predicted 11% and 12% of the variance intoddlers’ MDI and language development scores,respectively – even after obstetric complications, birthweight, children’s gestational age at birth, andmaternal postpartum depression were taken intoaccount. Given the size of these effects as well as therelative dearth of research with respect to childhoodcognitive outcomes, this represents a particularlyfruitful area for future investigation.



It is important to note that although the MDI is awidely used standardized tool for the assessment ofcognitive development in infants and young children,the predictive value of the MDI to cognitive func-tioning at later ages is not strong. Thus, establishingthat these prenatal experiences are associated withcognitive functioning in middle childhood, a point atwhich individual differences in cognitive abilities aremore differentiated and stable, is an important nextstep.

It is also of interest that in one recent study offinancially and emotionally stable women, therewas a small but significant positive association be-tween antenatal stress and both the MDI andphysical developmental index (PDI) of the Bayley(DiPietro, Novak, Costigan, Atella, & Reusing,2006). The authors suggested that a small to mod-erate amount of antenatal stress may actually behelpful for the development of the child, and thatperhaps the association between prenatal stress orarousal and child outcomes is best represented by au-shaped curve.

Infant and childhood outcomes: laterality andother neurodevelopmental disorders. In additionto the social and cognitive developmental outcomes,some studies suggest that antenatal stress predictsalterations in another index of neurobehavioral or-ganization, laterality (Weinstock, 2001; Kofman,2002). Glover, O’Connor, Heron, and Golding (2004),for example, observed that maternal reports ofanxiety (but not depression) at 18 weeks’ gestationpredicted an increased likelihood of mixed-handed-ness when children were 42 months of age (OR ¼1.23). This finding was observed over and above theeffects of parental handedness, obstetrical and otherantenatal risks, and postnatal anxiety. In anotherlarge-scale prospective study, Obel, Hedegaard,Henriksen, Secher, and Olsen (2003a) also showedthat antenatal life events were associated with ahigher prevalence of mixed-handedness duringchildhood. However, unlike Obel et al. (2003a), theseinvestigators found that maternal reports of lifeevents later in pregnancy (greater than 30 weeks’gestation) had greater predictive power than reportsgiven earlier in pregnancy (less than 12 weeks’ ges-tation). Despite this difference, the findings fromboth studies were similar in that they demonstratedlinks with mixed- as opposed to left-handedness.

Examination of such outcomes may be a particu-larly fruitful area for future research, as atypicallaterality has been observed in children with autism,learning disabilities, and other psychiatric condi-tions, including problems with attention and schi-zophrenia (Glover et al., 2004). Indeed, a recentstudy has shown that prenatal stress, especially at25–28 weeks’ gestation, is associated with an in-creased risk of autism (Beversdorf et al., 2005). It isan interesting possibility that many of these symp-toms or disorders, which share neurodevelopmental

components such as mixed-handedness, may beexacerbated by antenatal maternal stress.

Adult outcomes

Antenatal stress has also been associated with al-tered adult outcomes, although here, studies havefocused almost exclusively on psychopathology.Maternal exposure to traumatic events during preg-nancy, for example, has been associated with in-creased lifetime risk of developing psychiatricdisorders. In a retrospective cohort study, Van Osand Selten (1998) demonstrated that the offspring ofwomen who were pregnant during the Germaninvasion of the Netherlands in 1940 were at a signi-ficantly increased risk for developing schizophreniain adulthood (OR ¼ 1.5). These results were replic-ated among a sample of Dutch adults whose motherswere pregnant during a devastating flood in 1953(Selten, van der Graaf, van Duursen, Gispen-deWeid, & Kahn, 1999). Comparison samples in thesestudies included cohorts of individuals born prior toand following the disastrous event, in order to con-trol for its subsequent effects on socioeconomic sta-tus and other large-scale societal changes.Additionally, a higher incidence of affective disorderswas observed among a sample of Chinese adultswhose mothers were pregnant during a severeearthquake in 1976 (Watson, Mednick, Huttunen, &Wang, 1999). These studies, however, may under-estimate the magnitude of the relation between pre-natal stressors and adult psychopathology becausethe incidence of the disorders was obtained fromgovernment hospital records and analyses wereperformed on the most severely affected individualsin the selected populations.

Magnitude of effects of antenatal stress on childneurodevelopment

The size of the effects found in many of these stu-dies is considerable. Van den Bergh and Marcoen(2004) found that maternal anxiety during preg-nancy accounted for 22% of the variance in symp-toms of ADHD in 8–9-year-old children. In addition,exposure to stressful events doubled the risk forADHD problems in a study by Obel et al. (2003b).Huizink and colleagues (2003) found a smaller ef-fect, with 3–8% of the variance in mental and motordevelopment at 8 months explained by anxietyduring pregnancy. LaPlante et al. (2004) showedthat the level of prenatal stress exposure accountedfor 11% and 12% of the variance in the toddlers’Bayley MDI and productive language abilitiesrespectively, and accounted for 17% of the varianceof their receptive language abilities. Bergman,O’Connor, and Glover (in preparation) also observedan effect of antenatal life events at 18 months ofage, accounting for 22% of the variance in BayleyMDI scores.



O’Connor et al. (2002) and O’Connor, Heron,Golding, and Glover (2003) found that women in thetop 15% for symptoms of anxiety at 32 weeks’ ges-tation had double the risk of having children withbehavioral problems at 4 and 7 years of age, evenafter allowing for multiple covariates. It raised therisk for a child from this group of women havingsymptoms of ADHD, anxiety or depression, or con-duct disorder from 5% to 10%. This implies that theattributable load in behavioral problems due toantenatal anxiety is of the order of 15%. If we wereable to substantially reduce stress in pregnant wo-men, such findings suggest that this may have animportant effect on social and cognitive develop-mental outcomes.

Most of these are substantial effects, but thereremains considerable variation across children.Bergman, for example, has found that althoughantenatal maternal stress increases the risk for bothcognitive delay and elevations in anxiety, these donot necessarily occur in the same children (unpub-lished). It is likely that there are gene–environmentinteractions (Caspi et al., 2003) so that the effects ofantenatal stress become apparent among thosechildren who also have specific genetic vulnerabili-ties.

Is this fetal programming?

The studies described have all reported associationsbetween antenatal stress and a range of negativesequelae in children. However, this in itself does notprove that fetal programming is occurring. Therecould be other maternal and child effects that ac-count for these associations, ranging from sharedgenetic variance to indirect behavioral mechanismsof influence. For example, a mother who experiencesanxiety during pregnancy may have manifested thesame level of anxiety preconception. In this case, themechanism of transmission would be the transfer ofgenetic susceptibility to psychopathology as opposedto exposure to prenatal stress.

Additionally, if a mother is stressed during preg-nancy, she may also continue to be stressed duringthe postpartum period, thus affecting parentingquality. Stress in the pre- and postnatal period couldalso affect maternal perceptions of child behavior.Results from studies in which independent obser-vations of child behavior, as opposed to maternalreport, were found to be associated with prenatalstress provide some refutation of a maternal biashypothesis (Brouwers et al., 2001; Field et al., 2002).There remain, however, a number of potential thirdvariables that might explain the apparent associ-ation between prenatal stress and child outcomes,such as maternal use of cigarettes or alcohol duringpregnancy. Most studies, although not all, havecontrolled for these influences, which also have adirect effect on the development of the fetus. The bestevidence for an antenatal effect of psychological

stress comes from those studies in which theassociation between prenatal stress and child out-comes remains even after controlling for maternalpostnatal anxiety or depression (O’Connor et al.,2002; Van den Bergh & Marcoen, 2004; Brouwerset al., 2001). Bergman, O’Connor, and Glover deter-mined the frequency of both antenatal and postnatallife events, and found that the reduction in BayleyMDI scores was associated only with the antenatallife events (unpublished). These studies do providesome support for the concept of fetal programming.Recent work with rodents, however, suggests thatlong-term behavioral outcomes are determined bycharacteristics of both the pre- and postnatal envir-onment (Francis, Szegda, Campbell, Martin, & Insel,2003). The interactive effects of pre- and postnatalenvironmental influences have not yet been ex-amined in human populations, but represent a veryimportant area for future investigation.

Methodological problems and unansweredquestions

Sample sizes vary considerably in these studies andhave predictable effects on the methods used forassessment and analysis. Whereas larger studieshave relied upon maternal reports for ratings ofantenatal stress as well as the developmental out-come of interest, the smaller studies more frequentlyemploy observational measures (LaPlante et al.,2004; Van den Bergh & Marcoen, 2004). Despitesuch variations in sample size and methodologicalapproaches, the studies collectively suggest thatmaternal stress during pregnancy is a non-specificrisk factor for negative outcomes during childhood.

Almost all studies in this literature have measuredantenatal stress using self-reports. There is variationin the type of questionnaire administered, however,as some studies assessed daily hassles (Huizinket al., 2003), whereas others focused on life events(Lou et al., 1994; LaPlante et al., 2004; Obel et al.,2003a), perceived stress (Huizink et al., 2003;Rodriguez & Bohlin, 2005), or pregnancy-specificworries (DiPietro et al., 2006). However, these stud-ies do suggest that developmental effects can beobserved with relatively low levels of anxiety and/orchronic stress, at least for the kinds of social/emo-tional and cognitive outcomes investigated.

There is still much to learn about the types ofantenatal emotional disturbance or stress that ismost harmful for fetal and child development and thecontexts in which such effects may be attenuated.None of the published studies have employed clinicalinterviews, and it is not known whether specific sub-types of maternal psychopathology (e.g., phobia,generalized anxiety disorder, post-traumatic stressdisorder (PTSD)) differentially predict postnatal out-comes. This is important, as different biologicalprofiles are associated with different types of psy-chopathology – particularly with respect to func-



tioning of the HPA axis, a system purported to ex-plain relations between antenatal stress and thetypes of postnatal outcomes previously described(see next section). For example, lower concentrationsof cortisol secretion have been associated with PTSD,whereas higher concentrations have been associatedwith generalized anxiety disorder as well as depres-sion (Golier & Yehuda, 1998; Yehuda, Teicher,Trestman, Levengood, & Siever, 1996; Hoehn-Saric,McLeod, Lee, & Zimmerli, 1991). There is someevidence that levels of maternal self-reported anxietypredict child outcomes more strongly than depres-sion. For example, O’Connor et al. (2002) found thatalthough antenatal depression was associated withchild behavioral problems in a similar way to pre-natal anxiety, the associated effect size was smaller.The authors also found that the association betweenantenatal anxiety and child behavioral problems wasseparate and additive to the effects of postnataldepression (O’Connor, Heron, & Glover, 2002).

There is some indication that specific types of lifeevents that occur during pregnancy predict effectson the developing child. For example, children ofmothers who report undergoing a separation or di-vorce during pregnancy or experienced ‘cruelty bythe partner’ were more likely to display lower scoreson measures of cognitive development (Bergman,O’Connor, & Glover, unpublished). This finding issimilar to an early study by Stott (1973), whichsuggested that continuing personal tensions (speci-fically marital discord) were a particular risk factorfor ‘neurological dysfunction, developmental delaysand behavior disturbance’ during childhood.

The extent to which antenatal stress differentiallyaffects the development of male and female childrenis not clear, because few studies report results foreach sex separately. The studies of O’Connor et al.(2002) and Van den Bergh and Marcoen (2004) didexamine both sexes, however, and found a greatereffect of antenatal anxiety on ADHD symptoms inboys than in girls at 4 years. However, in a follow-upstudy of these same children at age 7, the increasedrisk due to antenatal anxiety was similar for bothsexes, suggesting an interactive effect of gender anddevelopment (O’Connor, Heron, Golding, & Glover,2003). In another example, Catalano and colleagues(2005) reported that the fetal death sex ratio in Cali-fornia was increased formales over females 2 monthsafter the September 11, 2001 attacks in New YorkCity. Because sex ratios did not differ from expectedvalues 9, 10, or 11 months following the attacks,decreases in conception rates do not appear toaccount for this finding. Nonetheless, given thatantenatal stress is associated with risk for psycho-pathology, and that psychopathological outcomesare often characterized by skewed gender distribu-tions, this represents an important consideration toexplore in future investigations.

While mounting evidence points to an associationbetween prenatal stress and postnatal developmen-

tal outcomes, there is currently little agreementabout the gestational age most sensitive to suchstress. Of the four studies that investigated symp-toms of ADHD, for example, one found some evid-ence for greater sensitivity during the first trimester(Rodriguez & Bohlin, 2005), two during mid-gesta-tion (Van den Bergh & Marcoen, 2004; Obel et al.,2003b) and one during late gestation. There areseveral possible reasons for these discrepancies. Oneis that the temporal boundaries of stressful experi-ences are, in many instances, difficult to quantify.For example, events that are acute in onset (e.g.,natural disasters, death of a family member) oftenlead to enduring changes in the surrounding envir-onment, which may be subsequently appraised asstressful. Additionally, maternal reports of anxietyand depression as well as daily hassles are charac-terized by their chronicity, rendering it difficult toquantify the onset and offset of the stressful experi-ence. Also, studies differ in terms of the timing of thegestational assessments. In O’Connor et al. (2002),for example, anxiety was measured at 18 and32 weeks’ gestation, and the associations werestronger with the latter time point. It remains poss-ible that the effects were actually maximal at mid-gestation, and this would concur with the findings ofother studies. Moreover, smaller-scale studies maynot have enough power to effectively examine theissue of sensitive periods during pregnancy withrespect to stress. More research is clearly neededto address these issues.

Underlying mechanisms: HPA axis andassociated biological processes

Investigators have focused primarily on the hypo-thalamic-pituitary-adrenal (HPA) axis in bothmother and child as the primary biological mech-anisms underlying the long-term effects of prenatalstress. The HPA axis is linked with relevant behavi-oral outcomes (Gunnar, 2001) and much animalwork has shown its susceptibility to the long-termeffects of early developmental experience (Levine,2005). Indeed, in several animal species, disruptionsin early caregiving are associated with permanentalterations in the dynamics of this axis, a systemthat is critically involved in preserving physicalhealth as well as mobilizing energy stores, promotingviligence, and inhibiting inflammatory responsesunder conditions of stress and threat (Gunnar,2003). Further, early postnatal experiences havebeen shown to affect the developing cortico-limbiccircuits involved in the regulation of the HPA axis,thereby rendering animals more vulnerable to effectsof subsequent stressors (Gunnar & Talge, in press).Specifically, the activation of the HPA axis is morepronounced and the response more prolonged.Moreover, a pattern of exhibiting heightenedbehavioral manifestations of anxiety in the response



to stressful stimuli persists into adulthood (e.g.,bodily stilling or freezing). Such chronic activation ofthe axis can be related to the development of healthproblems, and mounting evidence points to anincreased vulnerability to the development of psy-chopathology. Therefore, given the apparent relev-ance of early life experience to HPA and behavioralresponses to stressors, a burgeoning program ofresearch has examined the effects of prenatal stressin relation to this biological system as well as post-natal behavioral outcomes.

Evidence from animal models

In animal models, both rodent and non-humanprimate, the central role of the HPA axis in mediatingprenatal stress effects in both mother and offspringis well established (Weinstock, 1996, 2001; Schnei-der, Coe, & Lubach, 1992), although of course manyother neurocircuits, such as the dopaminergic andserotonergic systems, are also likely to be involved.

The most frequent techniques used to inducematernal stress in rats involve restraint (placing thepregnant rat inside a narrow, illuminated tube) orexposure to unpredictable bouts of loud noise. Bothprocedures produce reliable and significant in-creases in HPA activity in pregnant dams(Barbazanges, Piazza, Le Moal, & Maccari, 1996;Weinstock, Matlina, Maor, Rosen, & McEwen, 1992).Typically, these stress paradigms are administered3–5 times during the last week of pregnancy, cover-ing approximately 33% of fetal rat gestation. Com-parison groups include dams who remainundisturbed during their pregnancies, and offspringwho are cross-fostered to control for maternal post-natal behavior.

Elevations in maternal HPA activity caused byeither restraint or noise stress during pregnancyhave been associated with both short- and long-termeffects on developing offspring. For example, thisprenatal experience is consistently linked withsmaller size and head circumference at birth (Wein-stock, 1996). Prenatal stress exposure is also asso-ciated with altered HPA functioning and long-termbehavioral outcomes in the offspring. For example,restraint stress during pregnancy predicts higherbasal activity of the axis (Weinstock et al., 1992) aswell as potentiated and prolonged HPA responseswhen the offspring undergo restraint stress onpostnatal days 60 and 90 as adults (Weinstock et al.,1992, Vallee et al., 1997). These results are accom-panied by the downregulation of glucocorticoidreceptors (GRs) in the hippocampus and hypothal-amus (Barbazanges et al., 1996). However, GRs andcorticotropin-releasing-hormone (CRH) expressionin the amygdala were upregulated, a neurobiologicalprofile associated with anxiety-like behavior (Wein-stock, 1996). Indeed, prenatally-stressed offspringdisplay heightened behavioral responses to novelty,including freezing, decreased exploration, and

defecation (Vallee et al., 1997), behaviors that arealso associated with post-stress serum concentra-tions of cortisol. Disturbances in spatial memory andother aspects of cognitive functioning have also beenobserved (Chapillon, Patin, Roy, Vincent, & Caston,2002). Postnatal environmental enrichment, how-ever, does appear to reverse the effects of prenatalstress at the behavioral (Vallee et al., 1997; Maccariet al., 1995) and cognitive level (Bredy, Humpart-zoomian, Cain, & Meaney, 2003). Thus, in rodents,the postnatal environmental can influence themanifestation of prenatal stress effects.

In sum, the rodent literature suggests that prenatalstress is associatedwithmany long-termeffects in theoffspring, including behavioral hyper-arousal andimpaired cognitive functioning. These effects are inturn associated with altered function of the HPA axis,and its altered control by central glucocorticoids re-ceptors (Figure 1). Postnatal environmental enrich-ment, however, can mitigate these effects.

A series of developmental studies with non-humanprimates has also provided convincing evidence thatprenatal stress, and its associated increase inmaternal HPA activity, is related to both short- andlong-term negative sequelae in the offspring(Schneider et al., 2002; Clarke, Soto, Bergholz, &Schneider, 1996), including impairments in atten-tion as well as heightened levels of anxiety. Thecentral role of the maternal HPA axis has beendemonstrated (Schneider et al., 1992) as thesebehavioral effects can be replicated by administeringACTH to the pregnant monkey and abolished byadrenalectomy. Prenatal stress manipulations innon-human primates typically involve removingpregnant rhesus monkeys from their cages andsubsequently exposing them to uncontrollable, loudnoise bursts. These exposures typically occur onceper day, five days a week for approximately 25% ofgestation, and are associated with elevations in HPAactivity (Clarke et al., 1996). In several of thesestudies, prenatally stressed and control monkeyswere reared together in a nursery, irrespective oftheir prenatal experience, to control for postnataleffects of maternal behavior.

In terms of neonatal outcomes in the primate, nogroup differences in gestational length were observedas a function of prenatal stress exposure, althoughneonates tended to be smaller at birth (Schneideret al., 2002). Effects with respect to neurobehavioraloutcomes, which were measured during the firstmonth of life, depended somewhat upon the timing ofthe manipulation during pregnancy. Specifically,monkeys who were exposed to stress early in gesta-tion (days 45–90) often performed more poorly onmeasures of attention (e.g., visual orienting) andmotor maturity (e.g., head posture) than monkeysexposed during mid- to late gestation (days 120–134)or the undisturbed controls (Schneider, Roughton,Koehler, & Lubach, 1999). Mid- to late gestationalstress, however, was typically associated with poorer



neurobehavioral outcomes than was observed in theundisturbed pregnancies.

The effects of stress have also been observed underconditions of subsequent challenge at older ages,particularly in response to social separation. Al-though the effects of gestational timing are mixed,prenatally stressed monkeys tend to display height-ened ACTH, but not cortisol, responses to socialisolation at 8 months of age. Additionally, thesemonkeys display more pronounced behavioral dis-turbances (e.g., stereotypies) during this period ofisolation (Schneider et al., 2002). Prenatal stressalso affects behavioral responses to reunion withpeers, reflected by lower levels of locomotor activity,exploration, and play following their reintroductioninto the group. These behavioral results werereplicated when monkeys were 3–4 years of age, aperiod considered to be analogous to adolescence(Coe et al., 2003). Assessments at this stage havealso demonstrated that prenatal stress, irrespectiveof the timing during gestation, was associated withdecreased neurogenesis in the dentate gyrus as wellas a 10–12% decrease in hippocampal volume (Coeet al., 2003). This demonstrates that prenatal stressresults in relatively long-term effects on the brain aswell as behavior, particularly under conditions ofchallenge.

Finally, prenatally stressed monkeys mount amore prolonged HPA response to a pharmacologicalchallenge, suggesting impairment in the negativefeedback regulation of the system (Coe et al.,2003). The pathophysiology of this finding has yetto be examined, though it is plausible that highcirculating levels of maternal cortisol may down-regulate the expression of fetal hypothalamicglucocorticoid receptors as suggested by the rodentliterature.

The HPA axis as mediating mechanism in humans

There is much less understanding of the mechan-isms underlying the apparent effects of antenatalstress in humans, including the role of the HPA axisin mother or child. In one study, O’Connor et al.(2005) measured diurnal cortisol in 74 of the chil-dren of the ALSPAC longitudinal cohort at 10 yearsof age. Maternal antenatal anxiety at 32 weeks pre-dicted children’s morning cortisol concentrationsafter allowing for obstetric and socio-demographicfactors. There were no links between children’scortisol and maternal anxiety or depression ante-natally or postnatally. Huot, Brennan, Stowe, Plot-sky, and Walker (2004) showed that maternaldepression during pregnancy, but not postpartum,predicted the ratings of negative affect in the off-spring. In addition, cortisol levels in response to amild stressor at 6 months of age predicted negativeaffect in infants and toddlers. Both these studies arein agreement with animal findings.

In contrast to maternal depression, lower cortisollevels were observed among infants of motherswho developed PTSD in response to September 11

Figure 1 A model to show how antenatal stress mayaffect the function of the HPA axis, by a reduction inglucocorticoid receptors in the hippocampus, causingreduced negative feedback.The HPA axis is an elaborate system of checks andbalances that, beyond the maintenance of a circadianrhythm, allows mammals to adapt to changes in theirenvironment. The system is geared to respond rapidly tostressful stimuli, and then return to the baseline stateof homeostasis. Under stimulatory conditions neuronsin the paraventricular nucleus of the hypothalamus(PVN) secrete corticotropin releasing hormone (CRH)into the hypophyseal portal circulation. In the anteriorpituitary, CRH induces production of adrenocorticot-ropin (ACTH), which is released into the systemic cir-culation to stimulate formation and release ofglucocorticoids from the adrenal cortex (cortisol in hu-man and corticosterone in rat). Elevated serum gluco-corticoids provide the physiologic milieu required for anadaptive stress response, but also immediately begin tointeract with corticoid receptors to inhibit the stressresponse via negative feedback. Deleterious conse-quences of chronic exposure to stress or high levels ofglucocorticoids are well characterized, including struc-tural damage to key brain regions such as the hippo-campus. Therefore, the HPA axis needs to not onlyrespond swiftly to stress, but to terminate the stressresponse equally rapidly. Two steroid receptors mediateHPA negative feedback in the brain. The glucocorticoidreceptor (GR) demonstrates low affinity binding ofglucocorticoids operates within the range of the stressresponse. The mineralocorticoid receptor (MR) hashigher affinity to glucocorticoids and is vital in con-trolling basal HPA tone and the circadian rhythm. Whilethe PVN expresses predominantly GR, both receptorsare particularly enriched in hippocampus, which hasbeen implicated in mediating the neuronal aspects ofglucocorticoid feedback on the brain. Therefore, it isreasonable to assume that dysfunction in eitherreceptor system could severely affect the ability of ananimal to adapt to its environment. In the model ofepigenetic effects of prenatal stress on the hippocampalglucocorticoid receptors in the child proposed in thisreview, prenatal stress causes increased methylationfor the promoter region of the glucocorticoid receptor inthe hippocampus. This results in less transcription,fewer receptors, less feedback control and a greatercortisol response to stress. These effects may be modi-fied by maternal prenatal diet or immune status



compared to infants of mothers who did not developPTSD (Yehuda et al., 2005). Lower cortisol levelswere most apparent in infants born to mothersexposed in their third trimesters. The authors statethat ‘effects of maternal PTSD related to cortisolcan be observed very early in the life of the off-spring and underscore the relevance of in uterocontributors to putative biological risk for PTSD.’However, PTSD, unlike milder stress or anxiety, istypically associated with lower rather than highercortisol levels.

There is evidence of a strong correlation betweenmaternal plasma and fetal plasma cortisol levels(Gitau, Cameron, Fisk, & Glover, 1998; Gitau, Fisk,Teixeira, Cameron, & Glover, 2001), although fetallevels are about 10 fold lower than maternal levels.Thus, although the majority of maternal cortisol ismetabolized as it crosses the placenta, it appearsthat enough crosses into the fetal compartment tohave a clinically significant effect on fetal brain de-velopment. Clearly, the correlation between maternaland fetal cortisol levels in plasma does not prove thatthe mechanism by which prenatal stress affects thefetus is via maternal cortisol. Other explanations forthis correlation, such as a joint stimulation of corti-sol production in both mother and fetus by placentalCRH, are plausible. Recent results (Sarkar, BergmanO’Connor, Fisk, & Glover, unpublished) demonstratethat the correlation between maternal and fetal cor-tisol only becomes significant by mid-gestation.Thus, if maternal cortisol has an effect on fetaldevelopment earlier in gestation, the mechanismremains obscure.

Higher levels of self-reported stress have beenfound to be significantly associated with elevatedmaternal ACTH and cortisol concentrations at28 weeks’ gestation (Wadhwa et al., 2001), even aftercontrolling for obstetric complications. Combinedwith such demographic information as SES andrace, stress appraisals accounted for approximately36% and 13% of the variance in maternal ACTH andcortisol, respectively. In contrast, higher levels ofperceived social support have been found to beassociated with lower maternal levels of both ACTHand cortisol (Wadhwa, Dunkel-Schetter, Chicz-De-Met, Porto, & Sandman, 1996; Wadhwa et al., 2001).This raises the intriguing possibility that socialsupport, and the behavioral coping that it facilitates,buffers the maternal HPA axis (at least at the pitu-itary and adrenal levels) from activation in responseto stressful events.

Maternal stress during pregnancy has also beenassociated with alterations to the characteristicdiurnal rhythm of salivary cortisol. In one study,maternal reports of negative life events were com-pared to morning and evening samples of cortisolthat were collected at 14 and 30 weeks’ gestation.Results indicated that lower morning and higherevening values of cortisol were observed if mothersreported experiencing one or more negative life

events, irrespective of the timing during gestation(Obel et al., 2005).

Based on the animal literature, one would hypo-thesize that if the mother is stressed, her cortisolrises and this in turn crosses the placenta in suffi-cient concentrations to affect fetal development.However, some problems remain with this proposedmechanism in humans. For example, maternalcortisol responses to stress decrease markedlyacross gestation, such that by late pregnancy, thematernal HPA axis can be quite unresponsive. Thishas been shown in response to a pharmacologicalchallenge (Schulte, Weisner, & Allolio, 1990), aphysical challenge such as the cold pressor test(Kammerer, Adams, Castelberg, & Glover, 2002),and to the psychological stress of awaiting amnio-centesis (Sarkar, Bergman, Fisk, & Glover, 2006).Thus, at the time in pregnancy when there appearsto be the strongest link between maternal and fetalcortisol, the maternal HPA axis becomes less sensit-ive to stress. It remains possible that at around mid-gestation, the maternal HPA axis is still responsiveand there is passage of cortisol from mother to fetus.However, maternal cortisol is metabolized in theplacenta by 11bHSD-2, an enzyme that convertscortisol to its biologically inactive form, cortisone. Asa result, elevations in maternal cortisol are regulatedby concentrations of this enzyme, and consequentlylimit the fetus’ exposure to this hormone.

As discussed earlier, there is little agreement inthe literature about the period of gestation in whichmaternal stress is most harmful for the fetus. It isalso possible that some women and their infantsescape the desensitization of the HPA axis that nor-mally occurs with the progression of pregnancythrough differences in their genetic make-up andpsychological vulnerabilities. It is known that thereare polymorphisms in the glucocorticoid receptorthat are associated with different patterns of cortisolresponse to the same stressor (Wust, Federenko, vanRossum, Koper, & Hellhammer, 2005). It will beinteresting to examine these polymorphisms in bothmothers and children who appear vulnerable toantenatal stress.

Other possible mechanisms

This review has focused on the potential role of theHPA axis in mediating the link between maternalantenatal stress and an adverse neurodevelopmentaloutcome for the child. However, other mediatingmechanisms are possible; they just have not beenstudied in humans. For example, stress and anxietycause substantial activation of the sympathetic-adrenal system and this could also be important.Noradrenaline does not appear to cross the placenta(Giannakoulopoulos, Teixeira, Fisk, & Glover, 1999),but could affect the fetus indirectly by acting tocause contractions of the myometrium or by redu-cing uterine blood flow by affecting trophoblastic



invasion. There certainly appear to be rapid mecha-nisms linking maternal emotional state and fetalbehavioral and heart rate responses (e.g., Monk,Myers, Sloan, Ellman, & Fifer, 2003) which cannotbe explained by the slower responses of the HPAaxis. Additionally, given that the HPA axis functionsin concert with other biological systems of the body(e.g., sympathetic-adrenal axis), antenatal stress ef-fects are likely mediated by the dynamic interactionamong these systems.

Epigenetic mechanisms and possible influence ofdiet

Epigenetic mechanisms underlying the long-termeffects of perinatal stress have been studied inpostnatal rats. Meaney and colleagues have estab-lished a model showing the long-term effects of dif-ferent patterns of early maternal caregiving. Mothersthat carry out more nursing and licking have adultoffspring who are less anxious in behavioral testsand also have smaller and briefer HPA responses tonovel stressors (Zhang, Parent, Weaver, & Meaney,2004; Caldji, Diorio, & Meaney, 2000). Recently, thisgroup (Weaver et al., 2004) has shown that this in-creased nurturing is associated with less methyla-tion of the promoter region of the GR gene in thehippocampus. Methylation blocks transcription anddecreased methylation results in expression of moreGR receptors, more feedback control of the HPA axis,less corticosterone response to stress, and less an-xious behavior. It is interesting to note that mod-ifications in methylation were highly specific for bothgene and brain region. It is likely that similar epi-genetic modifications occur in the fetal brains ofprenatally stressed animals and humans, but thisremains to be determined.

Weaver et al. (2005) have also shown that one canincrease the methylation of the promoter region ofthe hippocampal GR receptor in this model by directinfusion of methionine, reversing the effect of ‘goodmothering’ and making offspring behaviorally hyper-aroused. It is suggested that methionine, a majormethyl donor normally supplied by protein, especi-ally in meat, may be modified by diet, altering theeffects of perinatal stress.

The hypothesis that diet may impact fetal pro-gramming is supported by studies of cardiovascularfunction in rodent models. Results from severalstudies demonstrate that if a pregnant rat is fed adiet low in protein, her adult offspring have alteredcardiovascular function and raised blood pressure(Langley & Jackson, 1994; Petry, Ozanne, Wang, &Hales, 1997; Brawley, Poston, & Hanson, 2003). Ofspecial relevance to the possible influence of diet onthe effects of prenatal stress are the experiments ofBertram, Trowern, Copin, Jackson, and Whorwood(2001). These authors showed that a low proteinmaternal antenatal diet decreased the expression of11ßHSD-2 in the placenta. This could potentially

result in the fetus being exposed to higher levels ofcortisol. A low-protein maternal diet also inducesincreased expression of GRs in the lung and kidneyof the offspring, thus potentiating the peripheraleffects of HPA activity.

Predictive adaptive response and evolutionarysignificance

Gluckman and Hanson (2005) have put forward theconcept of the ‘predictive adaptive response’ to ex-plain the evolutionary purpose of epigenetic fetalchanges in utero to prepare the offspring for theparticular environment in which it will find itself.Such changes can be much more rapid in responseto a changing environment than the natural selec-tion method based on genetic variation.

They suggest that early life responses occur in asingle generation to increase the chance of survivalof the individual to reproductive fitness. Thesechanges occur early in development when the indi-vidual is most plastic. In mammals, this is primarilyduring embryonic and fetal life. Hanson and Gluck-man discuss the example of the large fluctuations inpopulation numbers of snowshoe hares in NorthAmerica. When food is scarce, for example after alate spring, the population declines and many die ofstarvation. The fewer numbers mean that theremaining animals are more likely to be killed bytheir natural predators such as the lynx or coyote.The remaining hares must be extremely vigilant.Because the female hares are stressed, they havehigh cortisol levels during pregnancy; this in turnalters the function of the HPA axis of the offspringmaking them more vigilant and aware of the poten-tial threat from potential predators. This will helpthem to survive until food supplies increase andpopulation numbers can increase.

This type of fetal adaptive response to stressfulsurroundings has presumably developed in prim-ates, including humans, also. We can speculatethat extra vigilance and rapid shifts in attentioncould be adaptive in an environment full of dangeror predators. In our own civilization, with no pred-ators, and in which great premium is put in edu-cation on focus and concentration, extra vigilanceand rapid shifts in attention can be maladaptive,and result in unnecessary anxiety and problemswith attention.

Future research

There are many important ways in which this area ofresearch can and should be developed. All theexisting studies linking antenatal maternal stressand adverse child neurodevelopmental outcomeshave been carried out in Europe and North America.The stress experienced by women in their everydaylives in the developing world may be much harsher



and the outcomes for their children deserve study.The effects of other stresses such as war and politicalconflict on pregnant women and their future childrenare also likely to be severe and need to be under-stood. Based on the fact that similar levels of pre-natal stress result in a variety of behavioraloutcomes, we know that antenatal stress does notaffect all children in the same way. It is important tounderstand more about genetic and other vulner-ability factors as well as the protective effects ofprenatal and postnatal environments, and alsomechanisms of resilience. The implication of theexisting research is that intervention during preg-nancy to reduce stress or anxiety during pregnancyshould reduce the incidence of emotional and cog-nitive problems in the child and later adult. Thepotential efficacy of different types of such interven-tions still needs to be explored.

We also need to understand much more about thehormonal and other mechanisms underlying theseeffects and the gestational ages of vulnerability. Thiswill help to design the timing of effective antenatalinterventions and help researchers better charac-terize the biological and hormonal milieu withinwhich the fetus is developing. There can be a disso-ciation between self-reports of psychological distressand changes in levels of hormones such as cortisol. Itwould also be of interest to use other approaches toexamine fetal and neonatal development such asMRI, which may both show effects of prenatal stressand be used to demonstrate the efficacy of inter-vention. It is quite possible that the effects of pre-natal stress are moderated by other aspects of theenvironment such as maternal diet and immunestatus, and this has yet to be studied.

Acknowledgements

We would like to acknowledge the invaluable input ofall the members of the Early Stress, TranslationalResearch and Prevention Science Network in thewriting of this review, including: K.S. Anand, RonaldBarr, Alice Carter, Christopher Coe, Michael Geor-gieff, Vivette Glover, Megan Gunnar, Kate Keenan,Seymour Levine, CatherineMonk, Charles Neal, PeterNathanielsz, Paul Plotsky, John Stead, Nicole Talge,Delia Vazquez, and PathikWadhwa. The networkwassupported by the NIH grant R21 MH068489-01 toDMV and CRNJ. We would also like to extend ourthanks to Dante Cicchetti for his helpful commentsand advice, and to Tom O’Connor for his large con-tribution to VG’s understanding of this subject.

Correspondence to

VivetteGlover, Institute of Reproductive andDevelop-mental Biology, Imperial College London, Du CaneRoad, London W12 ONN, UK; Email: [email protected]

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